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Environ Health. 2008; 7: 50.
Published online Oct 22, 2008. doi:  10.1186/1476-069X-7-50
PMCID: PMC2577708
Potential developmental neurotoxicity of pesticides used in Europe
Marina Bjørling-Poulsen,corresponding author1 Helle Raun Andersen,1 and Philippe Grandjean1,2
1Department of Environmental Medicine, University of Southern Denmark, Winslowparken 17, 5000 Odense, Denmark
2Department of Environmental Health, Harvard School of Public Health, Landmark Building 3E-110, 401 Park Drive, Boston, MA 02215, USA
corresponding authorCorresponding author.
Marina Bjørling-Poulsen: mbpoulsen/at/health.sdu.dk; Helle Raun Andersen: hrandersen/at/health.sdu.dk; Philippe Grandjean: pgrandjean/at/health.sdu.dk
Received August 26, 2008; Accepted October 22, 2008.
Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.
Pesticides are used widely in agriculture to maintain and increase crop yields, and they are also applied in homes and gardens. The annual application of synthetic pesticides to food crops in the EU exceeds 140,000 tonnes [1], an amount that corresponds to 280 grams per EU citizen per year. Despite European policies to reduce pesticide use, EU statistics data for 1992–2003 show that the annual pesticide consumption has not decreased [1]. A few hundred different compounds are authorised for use in all EU member states, but a similar number of pesticides is in current use in different EU countries and are being evaluated for possible authorisation in all of EU. Approximately 300 different pesticides have been reported as contaminants of food products of European origin [2]. Up to 50 percent of fruits, vegetables and cereals grown in the European Union are known to contain pesticide residues [2], but only a small fraction of pesticides in current use are included in the monitoring programmes. Nonetheless, one out of twenty food items is known to exceed a current EU legal limit for an individual pesticide [2]. Further, over 25% of fruits, vegetables, and cereals contain detectable residues of at least two pesticides [2]. Processed food and baby food are also commonly contaminated. In addition, other sources, such as contaminated drinking water, dusts and spray drift contribute to human exposures.
The total level of population exposures to pesticides in Europe is unknown, but data from US population studies show that the majority of the population has detectable concentrations of methyl phosphate, ethyl phosphate, and other pesticide metabolites in the urine [3].
Many pesticides target the nervous system of insect pests. Because of the similarity of neurochemical processes, these compounds are also likely to be neurotoxic to humans. This concern is of particular relevance to the developing human brain, which is inherently much more vulnerable to injury caused by toxic agents than the brain of adults [4]. During prenatal life, the human brain must develop from the ectodermal cells of the embryo into a complex organ consisting of billions of precisely located, highly interconnected, and specialised cells. For optimum brain development neurons must move along precise pathways from their points of origin to their assigned locations, they must establish connections with other cells, and they must learn to communicate with other cells via these connections [4-6]. All of these processes have to take place within a tightly controlled time frame, and each developmental stage has to be reached on schedule and in the correct sequence. If a developmental process in the brain is halted or inhibited, there is little potential for later repair, and the consequences may therefore be permanent [4,6].
Concerns in regard to developmental neurotoxicity due to pesticides have been fuelled by recent epidemiologic observations that children exposed prenatally or during early postnatal life suffer from various neurological deficits [7-12]. Urinary pesticide metabolite concentrations associated with adverse effects overlap with the ranges that occur in the general population [3]. Although the identity of the parent pesticides and the exact magnitude of causative exposures are unclear, these observations suggest that developmental neurotoxicity from pesticide exposure is a public health concern.
Despite the increasing recognition of the need to evaluate developmental neurotoxicity in safety assessment [13-15], only very few of the commercial chemicals in current use have been examined with respect to neurodevelopmental effects [16]. Validated rodent models exist, but they are considered expensive and are only infrequently used. According to the current EU Plant Protection Directive (91-414-EEC), a neurotoxicity test in hens is required only for organophosphates and some carbamates to assess the possible risk of delayed peripheral neurotoxicity following acute exposure.
From a public health viewpoint, the prevention of neurodevelopmental disorders is a priority; these disorders include learning disabilities, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, developmental delays, and emotional and behavioural problems. The causes of these disorders are unclear, and interacting genetic, environmental, and social factors are likely determinants of abnormal brain development [17]. Medical statistics data are difficult to compare between countries, but one report suggests that 17% of US children under18 years of age suffer from a developmental disability, in most cases affecting the nervous system [18]. In calculations of environmental burdens of disease in children, lead neurotoxicity to the developing brain is a major contributor [19]. Pesticide effects could well be of the same magnitude, or larger, depending on the exposure levels.
A recent review [16] listed 201 chemicals known to be neurotoxic in humans; only 5 of these substances have been firmly documented as causes of developmental neurotoxicity. Identification of human neurotoxicity was based on available evidence, including poisoning incidents described in the scientific literature, as identified from the Hazardous Substances Data Bank of the U.S. National Library of Medicine. Although published clinical information may not be representative for the relative neurotoxicity risks due to industrial chemicals, it is noteworthy that a total of 90 (45%) of the neurotoxic substances are pesticides. For these substances, only neurotoxicity in adults had been documented, thereby documenting that access to the brain is possible and may cause toxic effects. Given the vulnerability of the developing brain, it is likely that many of these substances will also be capable of causing developmental neurotoxicity [16]. Indeed, studies in laboratory animals support the notion that a wide range of industrial chemicals can cause developmental neurotoxicity even at low doses that are not harmful to mature animals [14,20].
Given the likely importance of pesticides in regard to developmental neurotoxicity in humans, this review focuses on pesticides approved for current use in Europe, i.e. either authorised or being evaluated for authorisation within the European Union (Table (Table1).1). Our literature search was conducted by similar means as the previous review mentioned above [16], but included relevant data from laboratory experiments. The pesticides are grouped in accordance with the likely mechanism of action or chemical similarity. We focus on substances with a primary application as pesticides and therefore exclude substances like nicotine, warfarin, and ethanol with other primary uses.
Table 1
Table 1
Neurotoxic pesticides, which are authorised or pending evaluation for authorisation in the EU
Search strategy and selection
We first identified pesticides that have caused neurotoxic effects in humans from the Hazardous Substances Data Bank (HSDB) of the U.S. National Library of Medicine [16]. We searched for the terms "pesticide" and "neuro*". From the list of substances obtained in this way, we identified the pesticides, for which neurotoxic effects in humans had been reported. In addition, we searched the U.S. National Institute of Occupational Safety and Health (NIOSH) – Pocket Guide to Chemical Hazards http://www.cdc.gov/Niosh/npg/npgsyn-p.html, using the search terms "pesticide", "insecticide", "herbicide", "fungicide", "fumigant", and "rodenticide" in combination with "central nervous system". The list of neurotoxic pesticides identified in this way was then compared to the current Annex 1 list (as of August, 2008) of pesticides authorised in the European Union according to Plant Protection Directive 91-414-EEC (an Excel data sheet with the status of active substances under EU review can be downloaded from http://ec.europa.eu/food/plant/protection/pesticides/index_en.print.htm). We chose pesticides with an Annex 1 status "in" or "pending" for consideration (Table (Table11).
For each neurotoxic pesticide in current use, we searched PubMed to identify published data on developmental neurotoxicity. We used pesticide synonyms, commercial names and the CAS number, in combination with each of the terms "neurotoxic", "neurotoxicity", "neurologic", "neurological" and "nervous system", and additional searches included the terms "prenatal", "pregnancy", "fetus", "fetal", "maternal", "developmental" and "child".
Organophosphate insecticides
Toxic mechanisms
The primary target of organophosphate (OP) insecticides is the enzyme acetylcholinesterase (AChE), which hydrolyses the neurotransmitter acetylcholine in both the peripheral and the central nervous system. OPs containing a P = O moiety are effective inhibitors of AChE, whereas OPs with a P = S moiety require bioactivation to form an "oxon" or oxygen analogue of the parent compound. Inhibition of AChE by OPs is obtained by the P = O moiety forming a covalent bond with the active site of the enzyme. The enzyme-inhibitor complex can become "aged" by a non-enzymatic hydrolysis of one of the two radical groups in the OP, and once the complex has aged, inhibition of AChE is irreversible (reviewed in [21]). Inhibition of AChE causes accumulation of acetylcholine at cholinergic synapses, leading to over-stimulation of muscarinic and nicotinic receptors. In addition, acetylcholine has important functions during brain development [22].
In severe cases of OP poisoning in adults (AChE inhibition exceeding 70%) [23], a "cholinergic syndrome" is elicited, including various central nervous system (CNS) effects such as headache, drowsiness, dizziness, confusion, blurred vision, slurred speech, ataxia, coma, convulsions and block of respiratory centre [24]. Some OPs can also induce a delayed neuropathy which does not involve inhibition of AChE but rather the neuropathy target esterase (NTE) [25,26]. The physiological functions of NTE are still unknown, and it is obscure how phosphorylation and aging of NTE leads to axonal degeneration [27].
The syndromes described above are observed only following high dose, acute exposures to OPs. Survivors recover from these syndromes, but it is likely that the exposure also produces long-term adverse health effects. In rats, a single high exposure to an OP can cause long lasting behavioural effects [28,29], and the same has been reported from several human studies (e.g. [30,31]).
The concern is growing that also chronic, low exposures to OPs may produce neurological effects, although the evidence remains somewhat equivocal (reviewed in [32-34]). Most studies have found an association of OP exposure with increased neurological symptom prevalence. As an example, Hispanic immigrant farm workers in the US have a poorer neurobehavioural performance than non-agricultural Hispanic immigrants. Within the group of agricultural workers there was a positive correlation between urinary OP metabolite levels and poorer performance on some neurobehavioural tests [35]. A cross-sectional study of pesticide applicators reported that neurological symptoms were associated with cumulative exposure to moderate levels of organophosphate and organochlorine insecticides, regardless of recent exposure history [36].
Acetylcholine and other neurotransmitters play unique trophic roles in the development of the CNS [37,38], and inhibition of AChE by OPs and the resulting accumulation of acetylcholine may then conceivably disturb this development. Still, developing rats recover faster from AChE inhibition than adults, largely due to the fact that developing organisms have a rapid synthesis of new AChE molecules [39-41]. It therefore seems that either developmental toxicity may be unrelated to AChE inhibition, or that even a brief period of AChE inhibition is sufficient to disrupt development [42].
Chlorpyrifos is the most extensively studied OP with respect to developmental neurotoxicity in laboratory models. Prenatal or neonatal exposure has been shown to cause a variety of behavioural abnormalities in both mice and rats, including changes in locomotor skills and cognitive performance [43-46]. At concentrations comparable to those found in human meconium [47], experiments on rat embryo cultures showed mitotic abnormalities and evidence of apoptosis during the neural tube development stage, and significant effects even at concentrations more than an order of magnitude below those present in human meconium [48]. However, exposure of rat foetuses to chlorpyrifos by maternal administration did not induce large immediate effects on brain development [49], but chlorpyrifos treatment during gestation, did cause deficits in brain cell numbers, neuritic projections, and synaptic communication, which emerged in adolescence and continued into adulthood. This finding indicates that chlorpyrifos exposure during gestation results in altered programming of synaptic development [50,51].
The window of vulnerability to chlorpyrifos extends into relatively late stages of brain development, and chlorpyrifos can induce neurobehavioural abnormalities during the second and third postnatal weeks in rat [43,52,53], corresponding to the neonatal stage in humans [54]. This period is outside the major phase of neurogenesis in most brain regions, but it is the period of peak gliogenesis and synaptogenesis; developing glia have been found to be even more sensitive to chlorpyrifos than neurons [55-57].
Deficits elicited by prenatal exposure to chlorpyrifos are evident even at exposures below the threshold for detectable AChE inhibition, i.e. far below the 70% inhibition of AChE required for systemic toxicity in adults [43-46,51]. These findings suggest that mechanisms other than inhibition of AChE activity may, at least in part, be responsible for the developmental neurotoxicity of chlorpyrifos.
The non-cholinergic mechanisms of chlorpyrifos are not clear, but a possible target may be the signalling cascades involved in neuronal and hormonal inputs, including the cyclic-AMP – protein kinase A cascade, receptor signalling through protein kinase C, and direct effects on the expression and function of nuclear transcription factors mediating the switch from proliferation to differentiation, including c-fos, p53, AP-1, Sp1 and CREB (Ca2+/cAMP response element binding protein) (reviewed in [42]).
The notion that chlorpyrifos may exert developmental neurotoxicity through mechanisms other than inhibition of AChE opens the possibility that OPs may have compound specific effects that may be unrelated to the common AChE inhibitory effect. For example, microarray analysis has shown that the two OPs, chlorpyrifos and diazinon, have many similar effects on gene expression in the neonatal rat brain, but also notable disparities. All of the changes in gene expression induced by the two OPs were observed with doses, which did not induce biologically significant AChE inhibition [58,59]. In neonatal rats, diazinon and chlorpyrifos elicit each their unique pattern of damage/repair and altered synaptic function, even though OPs as a class target neural cell development and ACh systems [60].
Thus, findings of OP induced developmental neurotoxicity through individual mechanism other than the common AChE inhibition complicate extrapolation of effects from one OP to another. The existence of clear effects of OPs at doses below the threshold for AChE inhibition clearly demonstrate that it is inadequate to use AChE measurements alone as a biomarker for defining safe exposure limits for developmental neurotoxicity of OPs [60].
Epidemiologic evidence
With respect to developmental neurotoxicity of OPs in humans, knowledge is still relatively sparse, and most studies reflect exposures to more than one pesticide.
In California, USA, an association was found between reflex abnormalities in neonates and increased concentrations of OP metabolites measured in the mother's urine during pregnancy [7]. In a follow-up of the same cohort, urinary dialkyl phosphate metabolite levels during pregnancy, particularly from dimethyl phosphate pesticides, were negatively associated with mental development in the children at 24 months of age. No associations were observed between neurodevelopment and metabolites specific to malathion and chlorpyrifos [8].
In a cohort study of mothers and infants in New York City, USA, maternal levels of chlorpyrifos above the limit of detection, coupled with low maternal levels of paraoxonase activity (an enzyme which hydrolyses certain OPs, including chlorpyrifos oxon), were associated with reduced head circumference in the infants [61]. In the same cohort, prenatal levels of OP metabolites in the mother's urine were associated with anomalies of primitive reflexes in the infants [9].
In another New York City cohort, prenatal chlorpyrifos exposures were found to be inversely associated with birth weight and length [62]. In a follow up of this study, the children's cognitive and motor development was examined at 1, 2 and 3 years of age. The adjusted mean 3-year Psychomotor Development Index and Mental Development Index scores of the highly exposed children differed by 7.1 and 3.0 points, respectively, from the scores of children with low prenatal exposure to chlorpyrifos. The proportion of delayed children in the high-exposure group, compared with the low-exposure group, was five times greater for the Psychomotor Development Index and 2.4 times greater for the Mental Development Index [10].
Ecuadorian schoolchildren, whose mothers had been exposed to OPs and other pesticides during pregnancy by working in greenhouses, showed visuospatial deficits compared to children, whose mothers had not been exposed to pesticides during pregnancy. Furthermore, current exposure of the children, measured as the excretion of OP metabolites in urine, was found to be associated with increased reaction time [11].
In two US states, Ohio and Mississippi, children were acutely exposed to the OP, methyl parathion, and when analysed for neurobehavioural development, the exposed children were found to suffer from persistent problems with short-term memory and attention [12].
Although the epidemiological evidence for developmental neurotoxicity of OPs in humans is relatively sparse, there are clear indices of adverse effects. Urinary pesticide metabolite levels in the above studies were similar to those that have been recorded from the US general population [3,63] and in EU countries [64-66].
Carbamate insecticides
Carbamate insecticides, like the OP insecticides, inhibit AChE and elicit cholinergic hyperstimulation. However, carbamates cause only reversible inhibition of AChE [67]. Thus, AChE inhibition by carbamates lasts only minutes or hours, whereas the effects of OPs with respect to AChE can last for 3–4 months (reviewed in [32]). Because of the transient inhibition of AChE, acute intoxication by carbamates generally resolves within a few hours [67].
When comparing the clinical course of carbamate poisoning (by aldicarb or methomyl) in young children (1–8 years old) and adults (17–41 years old), it was found that the predominant symptoms in children were CNS depression and hypotonia, and the most common muscarinic effect was diarrhoea. In adults the main symptoms were miosis and fasciculations, whereas CNS depression, hypotonia, and diarrhoea were uncommon [68]. Symptoms in children poisoned with OPs were found to be similar to symptoms for carbamate poisoning [69]. Thus symptoms of carbamate poisoning do not differ markedly from symptoms of OP poisoning in children, but rather the symptoms in children, differ from symptoms in adults.
It is possible that some carbamates may also be involved in oxidative stress [70,71]. The carbamate, carbofuran, has been observed to accentuate oxidative stress in rat brain by inducing lipid peroxidation and diminishing the antioxidant defence [70].
As for the OPs, it is likely that poisoning with carbamates may result in long term neurological effects [72]. Two patients showed cognitive deficit in attention, memory, perceptual, and motor domains 12 months after a poisoning incident [72]. With respect to long term, low level exposures to carbamates, reports concerning chronic toxicity are almost non-existent.
No epidemiological studies of developmental neurotoxicity of carbamates in humans could be found, and data from animal experiments are very sparse as well.
Assuming that some of the neurotoxic effects observed in association with prenatal exposure to OPs, such as chlorpyrifos, are due to inhibition of AChE, it is possible that carbamates may have similar developmental effects, even though the inhibition of AChE by carbamates is only transient. Induction of oxidative stress by some carbamates might also cause developmental neurotoxicity. It should also be noted that the carbamate physostigmine inhibits DNA synthesis in undifferentiated neuronotypic PC12 cells (a standard in vitro model for neuronal development). When differentiation was induced, adverse effects on DNA synthesis were intensified, and effects on cell number after prolonged exposure were also worsened by differentiation. Furthermore, differentiating cells displayed signs of oxidative stress, as measured by lipid peroxidation. Finally, the transmitter fate of the cells was shifted away from cholinergic phaenotype toward the catecholaminergic phaenotype. Similar findings were made when incubating the cells with the OPs chlorpyrifos, diazinon and parathion [73].
Pyrethroid insecticides
The pyrethroids are a class of insecticides derived from naturally occurring pyrethrins from the Chrysanthemum genus of plants [74]. Pyrethroids contain several common features: an acid moiety, a central ester, and an alcohol moiety. Several stereoisomers exist of each pyrethroid compound, and their effects are stereospecific, indicating presence of specific binding sites (reviewed in [75]).
The acute toxicity of pyrethroids is mainly mediated by prolongation of the kinetics of voltage-gated sodium channels, which are responsible for generation of the inward sodium current that produces the action potential in excitable cells. Specific interaction of pyrethroids with the sodium channel slows down both the activation and inactivation properties of the channel, leading to a hyperexcitable state. Although activation is slowed at the single channel level, the density of sodium channels in excitable cells is so high that there are always sufficient unmodified channels to ensure that the activation phase of the action potential is not delayed. However, in the falling phase of the action potential, even a low proportion of modified channels can generate enough extra current to delay inactivation. This delay causes prolonged depolarisation, which, if the current is large enough and lasts long enough for neighbouring unmodified channels to recover excitability, can trigger a second action potential (reviewed in [76]).
Two types of pyrethroid structures exist. The type II pyrethroids contain a cyano-group in the α-position, whereas type I pyrethroids do not contain a cyano-group [77]. The two types differ with respect to the toxic signs they produce in rats, and with respect to the prolongation time of the sodium current they induce. Type I compounds prolong channel opening just long enough to induce repetitive firing of action potentials (time constants less than 10 msec), whereas type II compounds (time constants of more than 10 msec) hold the channels open for so long that the membrane potential ultimately becomes depolarised to the point at which generation of action potentials is no longer possible (reviewed in [75]).
Human pyrethroid poisoning is rare, and almost entirely involves type II pyrethroids. The main adverse effect of dermal exposure to type II pyrethroids is paresthesias, presumably due to hyperactivity of cutaneous sensory nerve fibres. Dizziness, headache and fatigue are common symptoms following ingestion of type II pyrethroids. In severe cases coma and convulsions are the principal life-threatening features [77].
The effects of pyrethroids on the CNS are complex and may also involve antagonism of γ-aminobutyric acid (GABA), modulation of nicotinic cholinergic transmission, enhancement of noradrenalin release, and direct actions on calcium or chloride ion channels. Still, because neurotransmitter-specific pharmacological agents do not protect very well against pyrethroid poisoning, it is unlikely that any one of these effects represents a primary toxic mechanism of action of pyrethroids. More likely, they are secondary to the effects on sodium channels, since most neurotransmitters are released secondary to increased sodium entry (reviewed in [76]).
In the few existing accounts of poisonings of adults with pyrethroids, successful recovery after the acute phase of poisoning has been described [78,79]. However, no detailed neuropsychological testing was applied to these patients, and also no post mortem examinations have been reported, and therefore it is unknown if such poisonings may have lasting effects. Likewise, no information is available on long term effects of low level chronic exposure in humans.
Neonatal rats are 4–17 times more vulnerable to the acute toxicity of pyrethroids (including permethrin (type I), deltamethrin (type II), cypermethrin (type II)) than adult rats [80,81]. The higher toxicity in neonates is affected by the lower capacity for metabolic detoxification, since neonates and adults have similar brain concentrations at different, but equitoxic, doses [80]. However, another study did not observe any age-dependency of the toxicity of the two type I pyrethroids, cismethrin and permethrin [82]. It has therefore been argued that age-dependent sensitivity to pyrethroids is only apparent at high acute doses, not at doses below those causing overt toxicity [82].
In addition to the possibility that young animals are more vulnerable to pyrethroids due to lower metabolic detoxification, there is also a possibility that increased vulnerability in young animals may be due to more specific effects of early life exposures. For example, several studies have found that embryonically expressed forms of voltage-gated sodium channels are replaced by adult forms as neurodevelopment proceeds (reviewed in[75]), and this difference in expression profile may affect the sensitivity towards pyrethroids. In mutation and knockout models of the voltage-gated sodium channels, perturbation of channel function during development impairs nervous system structure and function, underlining the importance of these channels in neurodevelopment. (reviewed in [75]).
Also in humans, perturbations of nervous system development have been associated with altered structure and function of voltage-gated sodium channels. Mutations in genes encoding sodium channel subunits have been identified, which result in neuronal hyperexcitability due to subtle changes in channel gating and inactivation [83]. Since pyrethroids also alter the activation and inactivation of sodium channels, and thereby the neuronal excitability, it is possible that these may have effects similar to mutations in the sodium channels. However, the mechanisms and magnitude of mutational versus pyrethroid effects are different, and also the duration of effect will differ (pyrethroids have a relatively short half-life, whereas mutations are permanent) [75].
Another possible indication that pyrethroid effects on sodium channels may be relevant to neurodevelopment is the observation that developmental exposure to phenytoin, an anticonvulsant that blocks sodium channels and other ion channels, disrupts nervous system structure and function [84]. The use of anticonvulsants during pregnancy has been associated with adverse effects, including microcephaly and intellectual impairment (reviewed in [75]). Although differences in doses and in pathogenesis may occur, this evidence would support a concern about the effect of pyrethroids on ion channels.
All existing studies of developmental neurotoxicity of pyrethroids were conducted with rodents as test animals, and although several of them have reported persistent changes in behaviour and/or neurochemistry in the animals, results appear somewhat inconsistent (reviewed in [75]). Several studies performed by Eriksson's group [85-87] have shown that mice exposed to pyrethroids on postnatal day 10–16 exhibit increased motor activity and a lack of habituation. These mice exhibit changes in density of muscarinic acetylcholine receptor (mAChR) binding for as long as 5 months after cessation of exposure [88]. Others have reported persistent changes in behaviour and/or biochemistry, including learning [89], motor activity [90], sexual behaviour [91], mAChR expression [92,93], and blood-brain barrier permeability [94]. A recent study in rats showed that neonatal exposure to permethrin and cypermethrin caused lasting behavioural effects, changes in monoamine concentrations in the striatum as well as increased oxidative stress [95]. In one study, both male and female mice were exposed to the type I pyrethroid, permethrin, before mating, and the following functions were affected in the offspring (with parental exposure to 9.8 mg/kg/day or more for 4 weeks before mating): development of reflexes, swimming ability and open field activity [96].
The potential developmental neurotoxicity of pyrethroids has also been investigated in vitro using cell lines. For example non-toxic concentrations (10-6 M) of bifenthrin inhibited neurite outgrowth in PC12 cells, indicating that bifenthrin may have deleterious effects on the developing nervous system at concentrations lower than those capable of causing toxicity in the adult brain [97].
Existing data indicate that human exposures to pyrethroids occur and result in detectable concentrations in body fluids [98-100], but there is insufficient information available to adequately evaluate the range of internal doses in humans, and the consequences of these exposures are so far unknown.
Dithiocarbamate fungicides
Dithiocarbamates are non-cholinesterase inhibiting, sulfur-containing carbamates, which are primarily used as fungicides and herbicides. Four major classes of dithiocarbamates exist; the methyldithiocarbamates, the dimethyldithiocarbamates, the diethyldithiocarbamates (DEDC), and the ethylenebisdithiocarbamates (EBDCs) (reviewed in [101]). The dithiocarbamates used as fungicides include metam sodium (methyldithiocarbamate), thiram (dimethyldithiocarbamate/tetramethyldithiocarbamate), and several EBDCs (mancozeb, maneb, metiram, zineb and nabam).
Dithiocarbamates form lipophilic complexes with di- and trivalent metallic cations, bonding through the sulfur atoms [102]. They are non-specific in action, and it is difficult to identify a single mechanism for their neurotoxic effects. Because of their metal-chelating capacity and their affinity for sulfhydryl groups, they are biologically highly active [103,104]. DEDCs are particularly known to modify the cellular redox state by inducing a copper-dependent oxidative stress [105,106], and inhibition of cytosolic Cu/Zn superoxidedismutase (SOD1), a key enzyme in the antioxidant response, has been observed in mice treated with DEDC [107]. The EBDCs can uncouple the mitochondrial electron transport chain [108,109]. Mitochondrial dysfunction is often associated with generation of reactive oxygen species (ROS), and ROS production was also found to play a role in mancozeb induced neuronal toxicity in mesencephalic cells, likely via redox cycling with extracellular and intracellular oxidases [110]. Further, ethylenethiourea (ETU), which is a degradation product of EBDCs, has been shown to inhibit thyroid peroxidase (TPX), the enzyme that catalyses synthesis of the thyroid hormones [111,112]. In addition, interference of dithiocarbamates with the vesicular transport of glutamate may play a role in their neurotoxicity [113]. Due to the differences in biochemical effects, these compounds seem to exhibit a range of different potencies in regard to developmental neurotoxicity.
Dithiocarbamates are reported to display low acute toxicity in humans and experimental animals [114]. Both in humans and laboratory animals, prolonged exposure to dithiocarbamates may cause neurotoxicity. Notably, peripheral neuropathy and extrapyramidal symptoms resembling parkinsonism have been associated with chronic exposure to dithiocarbamate pesticides [115].
As mentioned, chronic exposure of humans to EBDCs has been associated with neurocognitive impairment and parkinsonism [116]. In particular, exposure to maneb, which contains manganese, has been linked to development of parkinsonian-like symptoms in agricultural workers [117,118]. This finding may be related to the inhibition of complex III of the mitochondrial electron transport chain [108], disruption of the glutathione antioxidant system in dopaminergic cells [119], inhibition of proteasomal function and induction of α-synuclein aggregates in dopaminergic cells [120], induction of catechol autooxidation [121], and potentiation of the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice [122-124]. All of these observations support the notion that maneb may cause parkinsonian-like symptoms. DEDCs, though not methyldithiocarbamate, can also enhance MPTP- induced striatal dopamine depletion in mice [124].
Both thiram and ziram (dimethyldithiocarbamates) can induce apoptotic cell death in PC12 cells, in a dose- and time-dependent manner [125]. Both compounds induced rapid and sustained increases of intracellular Ca2+ in the cells, which were almost completely blocked by flufenamic acid, an inhibitor of non-selective cation channels. Also, BAPTA-AM, which is an intracellular Ca2+ chelator, inhibited the thiram and ziram induced apoptotic cell death, indicating that thiram and ziram induce apoptotic neuronal cell death by Ca2+ influx through non-selective cation channels [125].
The EBDCs maneb, mancozeb and metiram can induce malformations in rat foetuses, apparently mediated through formation of the ETU metabolite. The malformations predominantly affect the nervous system and the head, and they correspond to those expected as the result of thyroid insufficiency. They occur only at doses in excess of those that produce significant thyroid inhibition in adult rats, and they have been prevented, at least in part, by co-administration of thyroxin (reviewed in [126]). A key concern with thyroid inhibitors is that impaired thyroid function may alter hormone-mediated events during development, thereby possibly leading to permanent alterations in brain morphology and function [127,128]. Functional deficits are likely to occur during brain development even at mild degrees of hypothyroidism [129]. Even withing the normal range, a relatively slight reduction of the concentration of maternal thyroid hormones during pregnancy can lead to intelligence deficits in the children [130]. In addition to EBDCs/ETU, many other environmental contaminants have been found to interfere with thyroid function, for example the chlorophenoxy herbicide, 2,4-D (se below). Some of the mechanisms of action with respect to thyroid inhibition are shared by mancozeb/ETU and 2,4-D (including interference with uptake of iodide by the thyroid gland and interference with serum protein-bound iodide level) [131], and exposure to both EBDCs and chlorophenoxy herbicides may therefore result in additive effects.
Evidence that developmental exposure to maneb may be involved in development of Parkinson's disease (PD) later in life includes the finding that postnatal exposure of mice to maneb in combination with paraquat (a classic bipyridyl herbicide, which is no longer authorised in EU) led to a permanent and selective loss of dopaminergic neurons in the substantia nigra pars compacta [132]. The postnatal exposure to these pesticides enhanced the effect of the same pesticides administered during adulthood, relative to exposures during development only or adulthood only. Furthermore, exposure to maneb alone during gestation resulted in a dramatic response to paraquat in adulthood, including notable reductions in levels of dopamine and a loss of nigral dopamine neurons. Thus, these results support the notion that a silent neurotoxicity produced by developmental insults can be unmasked by insults later in life [132].
For specific dithiocarbamates, especially the EBDCs maneb and mancozeb, substantial evidence supports the possibility of developmental neurotoxicity. In addition, the likely mechanisms of toxicity for thiram and ziram indicate that these compounds too may be capable of causing developmental neurotoxicity in small doses.
Chlorophenoxy herbicides
The chlorophenoxy herbicides are widely used for the control of broad-leaved weeds. Structurally, they consist of a simple aliphatic carboxylic acid moiety, which is attached to a chlorine- (or methyl-) substituted aromatic ring by an ether bond. In vivo the salts and esters are rapidly dissociated or hydrolysed, and therefore the toxicity of each chlorophenoxy compound depends principally on the acid form of the pesticide [133]. The chlorophenoxy herbicides bind strongly to albumin [134], and binding is favoured by longer acid chains and by more greatly substituted aromatic rings. Therefore the bioavailability and toxicity of the herbicides vary for different herbicides [135]. The mechanisms of neurotoxicity of the chlorophenoxy herbicides are incompletely known, but they seem to primarily involve cell membrane damage (reviewed in [135]).
2,4-Dichlorophenoxyacetic acid (2,4-D) is the most widely used chlorophenoxy herbicide and also the most widely studied. With respect to membrane damage, it does not cause significant penetration of lipid monolayers in vitro at concentrations below 0,1 μM [134], but at higher concentrations (10–100 μM) it increases bilayer width and causes deep structural perturbations of the hydrophobic region of model membrane systems. At the higher concentrations it also damages human erythrocyte cell membranes [136]. This dose- dependent effect on plasma membranes may in part explain the dose-dependent CNS toxicity caused by chlorophenoxy herbicides. In experimental animals (rats, mice and rabbits), only small amounts of herbicide were found in the brain following administration of 100 mg/kg or less [137-139], likely because low concentrations of herbicide have little effect on the plasma membranes comprising the blood-brain barrier. When exposing rats to high doses (250–500 mg/kg) of the herbicide, a reversible selective damage to the blood-brain barrier occurred, and as a result serum albumin and IgG could be detected in the brain along with the herbicide itself [140]. The severity of the herbicide-induced cerebrovascular damage in rats has been reported to increase in the order 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) < MCPA (4-chloro-2-methylphenoxyacetic acid) < 2,4-D [141].
Chlorophenoxy herbicides can also disrupt cell membrane transport mechanisms. They competitively inhibit and ultimately saturate the organic anion transport system in the choroid plexus, which facilitates the removal of potentially toxic anions (including endogenous neurotransmitter metabolites and exogenous organic acids) [139,142,143]. Homovanillic acid and 5-hydroxy-3-indoleacetic acid, i.e. metabolites of dopamine and serotonin, respectively, accumulate in the CNS of rats following 2,4-D administration [144].
It has also been reported that 2,4-D induced neurotoxicity may be partly due to generation of free radicals. When incubating rat cerebellar granule cells with 2,4-D in vitro, glutathione (GSH) levels and catalase activity were significantly reduced, whereas generation of reactive oxygen species (ROS) and activity of selenium-glutathione peroxidase (Se-GPx) were augmented [145].
Furthermore, chlorophenoxy acids are structurally related to acetic acid and are able to form analogues of acetyl-CoA (e.g. 2,4-D-CoA) in vitro. Formation of such analogues has the potential of disrupting several pathways involving acetyl-CoA, including the synthesis of acetylcholine. Possible formation of choline esters (e.g. 2,4-D-Ach) may act as false cholinergic messengers (reviewed in [135]).
In cerebellar granule cells, 2,4-D produced a striking and dose-dependent inhibition of neurite extension, and in vitro 2,4-D inhibited polymerisation of purified tubulin. Thus, it was suggested that at least one mechanism of 2,4-D neurotoxicity involves inhibition of microtubule assembly [146]. Yet another study with cerebellar granule cells showed that 2,4-D induced apoptosis when cells were exposed to millimolar concentrations of the compound [147].
Chlorophenoxy herbicide poisoning in humans is uncommon, but it may produce severe sequelae. In a review of 66 cases of chlorophenoxy herbicide poisoning [135], the majority of cases involved ingestion of 2,4-D, either alone or in combination with other chlorophenoxy herbicides. Neurotoxic effects included coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculations, and paralysis. Some degree of peripheral neuromuscular involvement occurred in approximately one third of the cases reviewed. Still, other constituents, such as surfactants or solvents, in the formulations of the herbicides could possibly have contributed to some of the effects observed [135].
The information with respect to possible neurological effects of chronic exposures to low doses of chlorophenoxy herbicides is sparse, and in a review from 2002, it was concluded that it is unlikely that 2,4-D has any neurotoxic potential at doses below those required to induce systemic toxicity [148]. However, a cohort study suggested an increased risk of amyotrophic lateral sclerosis (ALS) among workers chronically exposed to 2,4-D, compared to non-exposed employees at the same company, although this conclusion was based on only three deaths [149].
Although neurotoxicity in adults from low, chronic exposures to chlorophenoxy herbicides has not been reported, developmental exposure to low levels of these herbicides may still pose a threat. One case of cephalic malformations and severe mental retardation has been observed in an infant whose parents received prolonged exposure to 2,4-D via the dermal route from forest spraying [150].
Evidence of developmental neurotoxicity of chlorophenoxy herbicides, in particular 2,4-D, has also been obtained from experimental animals. For example, external treatment of fertilised hens' eggs with 2,4-dichlorophenoxyacetic butyl ester produced hypomyelination in the chicks, and reductions in "myelin markers" (including sulfatides, cerebrosides and 2'3'-cyclic nucleotide 3'-phosphohydrolase activity) were seen in chick embryos even before the period of active myelination [151]. A deficit in myelin lipid deposition was also detected in neonatal rats exposed to 2,4-D through lactation [152]. Other findings in response to neonatal exposure of rats to 2,4-D through lactation include a delay in CNS development [153], an increase in size and density of serotonin immunoreactive neuronal somata as well as an increase in fibre length in the dorsal and medial raphe nuclei [154]; and oxidative stress in specific brain areas, including midbrain, striatum, and prefrontal cortex [155].
Behavioural effects in the offspring have also been reported following prenatal and continued exposure to 2,4-D [156]. Also following prenatal and continued exposure of rats to 2,4-D, even beyond lactation, the dopamine D2-type receptor was increased about 40% in the striatum. Increased levels of the receptor were also found in the prefrontal cortex and cerebellum. However, when discontinuing exposure after weaning, no differences in dopamine D2-type receptors could be detected compared to control rats, suggesting that the effects of 2,4-D on these receptors may be reversible [157].
Thus, even though the evidence is sparse, some chlorophenoxy herbicides, in particular 2,4-D, have neurotoxic potentials and may cause developmental neurotoxicity.
Bipyridyl herbicides
The bipyridyl herbicides share common toxic mechanisms [158,159]; paraquat has been used as a model substance, but is no longer allowed in the EU. Intracellularly, both paraquat and diquat undergo redox cycling, leading to the generation of superoxide anions. These anions may react to form hydrogen peroxide and subsequently the highly reactive hydroxyl radical, which may then cause lipid peroxidation and cell death [159,160]. Another factor contributing to toxicity is the depletion of nicotinamide adenine dinucleotide phosphate with a bound hydrogen ion (NADPH), as both herbicide redox cycling and hydrogen peroxide detoxification via glutathione are NADPH dependent [159,161]. In addition to redox-cycling, there is some evidence that paraquat may be able to interact with enzymatic targets in the CNS, such as AChE and butylcholinesterase [162].
The initial phase of moderate to severe intoxication with paraquat and diquat is characterised by renal and liver failure, but the subsequent clinical course differs between the two, with intestinal paralysis and fluid loss as prominent features of diquat intoxication [160,163-165]. In severe and usually fatal cases of diquat poisoning, coma has also been reported [160]. Severe neurological and neuropsychiatric complications due to brain stem infarction and/or intracranial haemorrhage have also been described [161,163,166].
In regard to long-term consequences of exposure to bipyridyl herbicides, paraquat is a prime suspect with respect to induction of PD. It causes selective degeneration of tyrosine hydroxylase immunopositive (TH+) neurons in the substantia nigra pars compacta, and long-term exposure has been found to increase the risk of PD in a Taiwan population that sprays paraquat on rice fields [167-169]. A case report has described PD following diquat exposure [170], but because of a long induction period and the difficulties in retrospective exposure assessment, the hypothesis of delayed appearance of degenerative nervous system disease is difficult to verify. Since both paraquat and diquat can generate the formation of ROS, these compounds may well be involved in neurodegenerative diseases other than PD, such as Alzheimer's disease, but little evidence is available to evaluate this potential.
Even though it is rather clear that the cytotoxicity of paraquat involves oxidative stress [171], the sensitivity of dopaminergic neurons is difficult to explain [172]. Possibly, the dopaminergic neurons may be particularly sensitive to the reactive oxygen species (ROS) from paraquat, since dopamine metabolism also creates ROS [173]. In mice treated with paraquat once a week for 3 weeks, the effect on catecholaminergic neurons was reminiscent of that in PD, with a preferential loss of dopaminergic neurons in the substantia nigra pars compacta. This is consistent with the results from several similar studies [168,169,171].
PD has also been explored as a relevant outcome with respect to developmental neurotoxicity. When neonatal mice were exposed to paraquat, a marked hypoactive condition was apparent at 60 days of age and became even more pronounced at 120 days of age [174]. Furthermore, paraquat reduced the striatal content of dopamine and metabolites without affecting serotonin [174]. As already mentioned above under dithiocarbamates, other evidence suggests that maneb and paraquat may jointly and individually induce loss of dopaminergic neurons in mice. Administration of these pesticides postnatally enhanced the effect of the same pesticides administered during adulthood. Furthermore, exposure to maneb alone during gestation resulted in a dramatically increased response to paraquat in adulthood, including notable reductions in levels of dopamine and a loss of nigral dopamine neurons [132]. Similarly, the greatest effect on locomotor activity in mice occurred in males after exposure to maneb prenatally and to paraquat in adulthood [175]. This finding was supported by decreased levels of striatal dopamine, increased striatal dopamine turnover, and selective reduction in tyrosine hydroxylase-immunoreactive neurons of the substantia nigra pars compacta.
These observations are in agreement with the notion that an initially silent toxicity was later unmasked, and was affected by the specific order-of-presentation of the pesticides in regard to the developmental stage (not just an effect of the combination of pesticides). Thus, it seems that prenatal exposure to maneb, rather than paraquat, may sensitise/predispose mice to development of PD (or lead to a state of increased vulnerability), whereas paraquat exposure later in life may unmask the silent toxic effect of the earlier maneb exposure and then lead to clinical symptoms of the disease. Therefore it is possible that in the case of PD, developmental exposure to paraquat may not be as damaging as later exposure, particularly if this later exposure follows developmental exposure to maneb.
Fumigants
The mechanisms of toxicity employed by various types of fumigants are poorly known. A common mechanism of action is not expected, and the fumigants are therefore reviewed one by one.
Among metal phosphide fumigants, aluminium phosphide is one of the most extensively used. The phosphides are very toxic, because of their ability to liberate phosphine under moist conditions (reviewed in [176]). Phosphine is a reductant and predictably reacts with metal ions such as the iron in haem and the divalent metals of metal dependent enzymes [177]. Cytochrome c oxidase, of the mitochondrial electron transport chain, has been suggested as the primary site of action for phosphine [176,178,179]. A 50% inhibition of this enzyme was found to be sufficient for generation of superoxide anions, and it was suggested that the toxicity of phosphine was due to damage by free radicals [178]. In agreement with this hypothesis, aluminium phosphide has been found to increase lipid peroxidation in rat brain [180].
Further, in 45 phosphine poisoning patients, increased levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were detected in non-survivors, while catalase was inhibited [181]. Oxidation of phosphine can lead to formation of reactive phosphorylating species [182], thus suggesting that effects on cholinesterase may be possible [183]. Studies of grain fumigant applicators [184] and in vitro studies of human red blood cells [185] have shown that significant phosphine-induced inhibition of red blood cell cholinesterase occurs at concentrations of phosphine exceeding 10 μg/ml.
Neurological changes like ataxia, stupor, tremors and convulsions have been observed following aluminium phosphide poisoning. Acute hypoxic encephalopathy has also been observed following aluminium phosphide poisoning, which may lead to death as a result of complete depression of the central nervous system and paralysis of the respiratory centres of the brain (reviewed in [176]).
With respect to consequences of chronic phosphide exposure knowledge is sparse, but one descriptive study reported that most of a group of workers exposed to zinc phosphide had one or more neuropsychiatric symptoms including anxiety, impotence and easy fatigue. About half of the workers showed hyperreflexia, polyneuropathy, lumbar radiculopathy, and cervical myelopathy, as well as anxious mood, impaired attention, and psychomotor stimulation. EEG recordings showed abnormal findings in 17.4% of the subjects, mainly those with longer exposure [186]. These preliminary findings should invite further studies in this area.
For the fumigant sulfuryl fluoride, very little is known concerning the mechanism of toxicity. The fluoride ion may play a role, since many of the observations in rodents overexposed to sulfuryl fluoride are typical of acute fluoride poisoning [187]. In humans, short-term inhalation exposure to high concentrations of sulfuryl fluoride has been reported to cause central nervous system effects [188]. A case report describes an elderly couple, who returned to their home 5–8 hours after fumigation with sulfuryl fluoride. The wife experienced weakness, nausea, and repeated vomiting, while the husband complained of dyspnea and restlessness. Within 48 hours the husband had a generalised seizure followed by cardiopulmonary arrest. The wife died within 7 days due to ventricular fibrillation. The serum fluoride concentration of the wife six days after the fumigation was reported to be as high as 0.5 mg/L [189].
Workers with a chronic, low level exposure to sulfuryl fluoride showed non-significantly reduced performance on all applied neurobehavioural tests compared to the control group in one study [190]. Education levels, ethnicity and drug use differed between the workers and the control group in this study. In a later study of structural fumigation workers [191], sulfuryl fluoride exposure during the year preceding the examination was associated with significantly reduced performance on the Pattern Memory Test (a test of cognitive and visual memory) and an olfactory test. No pattern of cognitive deficits was detected.
None of these fumigants has been examined in detail for possible developmental neurotoxicity. Pregnant rats and rabbits exposed to sulfuryl fluoride were reported to show no evidence of embryotoxicity, foetotoxicity, or teratogenicity at concentrations of sulfuryl fluoride as high as 225 ppm, although body weights of rabbit foetuses as well as the dams at the highest exposure were lower than in the control group [192].
In regard to phosphine, a large epidemiological study found that adverse neurological and neurobehavioural developmental effects clustered among children fathered by applicators of phosphine (odds ratio = 2,48; 95% confidence interval: 1.2, 5.1) [193]. Other than this study, no information regarding developmental neurotoxicity of phosphine was identified.
Other pesticides
The present review on neurotoxicity has focused on a small number of substances out of the total number approved for use as pesticides in the EU. Quite likely, much evidence exists on neurotoxicity, but has not been published in biomedical journals. Nicotine, warfarin and ethanol are additional well documented neurotoxicants, but their primary use is not as pesticides. The same applies to other substances listed, such as sodium hypochlorite and aluminium sulfate, which may potentially add to neurotoxic hazards.
Public health implications
Some of the substances belonging to the groups of pesticides reviewed here (including OPs, carbamates, pyrethroids, ethylenebisdithiocarbamates, chlorophenoxy herbicides, and bipyridyl herbicides) appear to share common mechanisms of action with respect to induction of neurotoxicity. Thus, members of these chemical groups of pesticides other than those identified as neurotoxic in the present review, would then be highly likely also to cause neurotoxicity. For other groups of pesticides without a plausible common mechanism of action (e.g. the fumigants), it is not possible to predict whether group members might share neurotoxicity potentials.
Further refinement of this prediction is difficult. As anticipated, the literature on developmental neurotoxicity is sparse for most of the pesticides. However, some evidence does exist to suggest that several of the neurotoxic pesticides in current use in the EU may cause developmental neurotoxicity in small doses. Table Table22 summarises the existing evidence of developmental neurotoxicity for groups of pesticides with common mechanisms of action.
Table 2
Table 2
Evidence of developmental neurotoxicity caused by pesticides belonging to groups with likely common mechanisms of neurotoxicity
Most evidence is available for the OPs, especially chlorpyrifos. The evidence strongly supports the notion that developmental neurotoxicity may be induced by very low exposure levels, i.e. much below those causing any neurotoxicity in adults. Most evidence still comes from studies in laboratory animals, but some epidemiological data are highly suggestive of neurotoxic effects caused by developmental exposure of humans to OPs (including chlorpyrifos). In the case of OPs, which share inhibition of AChE as a common mechanism of action in high doses, chlorpyrifos may employ other mechanisms of action at lower doses associated with developmental neurotoxicity. In fact developmental neurotoxicity in mice and rats can be induced at doses, which cause no detectable inhibition AChE [43-46,51]. Thus, even though a group of pesticides shares a common mechanism of action at larger doses, it cannot be excluded that compound specific mechanisms may also exist at lower doses. This fact unfortunately complicates the extrapolation of developmental neurotoxicity from one member of a group of pesticides to another. However, the combined human evidence on developmental neurotoxicity associated with OP exposure cannot be ascribed to chlorpyrifos alone.
Other than for OPs, the evidence of developmental neurotoxicity in humans is sparse, but evidence on developmental neurotoxicity in laboratory animals exists for pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides (mainly 2,4-D).
In the case of dithiocarbamates, evidence from laboratory animals suggests that developmental exposure to, e.g. maneb, may predispose the individual to development of PD later in life in response to another exposure, in particular paraquat. Other experimental studies suggest that prenatal exposure to paraquat can also predispose to development of PD later in life. It seems that the greatest effect of paraquat with respect to induction of PD is obtained from exposure later in life, following early priming exposure to maneb [175]. Although PD is a degenerative disease associated with aging, these data suggest that developmental exposure to pesticides (e.g. maneb) may constitute an aetiological factor that sensitises the individual to later insults (e.g. subsequent pesticide exposure, and aging).
For the remaining pesticides that belong to groups without a common mechanism of toxicity, the lack of research on developmental neurotoxicity complicates the evaluation of their safety. In a few cases (e.g. the fumigant sulfuryl fluoride), the existing evidence from animal experiments indicates that developmental neurotoxicity may be unlikely to occur at doses below those causing maternal toxicity [192,194]. Still, in these experiments, possible later emerging effects or sensitisation caused by developmental exposure has not been studied, so any conclusion in this regard would be tentative.
On the other hand, with respect to the metal phosphide fumigants, which release phosphine under moist conditions, some evidence of developmental neurotoxicity does exist. An epidemiologic study has found adverse neurological and neurodevelopmental effects among children fathered by applicators of phosphine [193]. For the remaining pesticides reviewed, no data from either human or animal studies could be located by our search.
This review has focused on those pesticides, for which human neurotoxicity has been reported in relation to specific exposures to the particular pesticide. This means that we have excluded poisoning cases involving more than one compound, where the contribution by each substance may be unknown. Thus, our list of neurotoxic pesticides is likely a substantial underestimate of the true number of neurotoxic pesticides. The fact that no poisoning incident with neurotoxic effects has been reported for a given pesticide is of course no guarantee that the pesticide is not neurotoxic, especially in regard to developmental exposure. A prudent evaluation of the evidence would therefore suggest that, if individual members of a chemical grouping of pesticides have been documented as neurotoxic, then all members of that group should be considered to be neurotoxic as well.
In addition to the problem of scarce – in many cases even non-existing – scientific evidence on developmental neurotoxicity of the pesticides in current use, some discrepancies exist between results of animal studies. An important factor in regard to apparent discrepancies is that the timing of exposure varies between studies. In some studies, animals are exposed prenatally, in other studies neonatally (during the first weeks of life), and in some studies both prenatally and neonatally. The timing of exposure may greatly influence the extent and type of neurotoxicity induced. Most animal studies have been performed in rodents, where brain development is mainly neonatal and spans the first three to four weeks of postnatal life [14,195]. Thus, although neurotoxic effects may be induced in rodents by only prenatal exposure, it is highly likely that these studies underestimate the neurotoxic effects, which may occur in response to prenatal exposure of humans, where the third trimester of pregnancy is a crucial period of brain development.
A further concern is that humans are very likely to be exposed to a number of pesticides and other neurotoxic compounds simultaneously. Because it is possible that some of these may have synergistic or additive effects, exposure to even very low doses during development may cause neurotoxic damage.
In addition to "direct" neurotoxicity, there is also evidence that several pesticides may indirectly cause neurotoxicity, e.g. by interference with thyroid function. Some 60% of all herbicides, in particular 2,4-D, acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, and thioureas have been reported to interfere with thyroid function (reviewed in[196]). In addition, EBDC dithiocarbamates, organophosphates and synthetic pyrethroids are thought to interfere with thyroid function (reviewed in [197]). A key concern with thyroid inhibitors is that impaired thyroid function may alter hormone-mediated events during development, leading to permanent alterations in brain morphology and function [127,128]. Other types of endocrine disruption can conceivably lead to neurobehavioural deficits, but this evidence has not been included here.
The current evidence can therefore be summed up as follows. A substantial proportion of pesticides in current use are known to be neurotoxic. However, neurotoxicity potentials of pesticides have not necessarily been examined, as legally mandated tests do not require specific assessment of neurotoxic potentials, apart from tests for peripheral neurotoxicity in hens required for OPs. A test battery for developmental neurotoxicity has only recently been completed by OECD, and very limited test data are available for pesticides. Because developmental neurotoxicity can occur at exposures much below those that cause toxicity to the adult brain, usage restrictions and legal limits for pesticide residues in food may not be sufficiently protective against developmental neurotoxicity. In addition, experimental, clinical and epidemiologic evidence supports the notion that neurotoxicity may be much more severe and possibly irreversible when the exposure occurs during early development.
Unless documentation exists for a particular pesticide to falsify this notion, all neurotoxic pesticides should be considered likely of inducing developmental neurotoxicity at low doses. The public health significance of this issue is illustrated by the epidemiologic observation of neurodevelopmental deficits at exposure levels that seem to be commonly occurring in the general population. Although the exact identity of the causative substances may be uncertain, pesticide contamination of foods is common in the EU, it often exceeds previously identified legal limits, and it involves substances that are known to be neurotoxic. Given the substantial impact of neurodevelopmental abnormalities in society and the likely impact of environmental aetiologies, prevention of pesticide exposure appears to be an obvious public health priority.
Given the widespread use and exposure to pesticides, the general lack of data on developmental neurotoxicity is a serious impediment. For certain pesticides, a requirement exists for neurotoxicity tests in adult animals, but developmental neurotoxicity is usually not considered when determining pesticide safety. Experimental, clinical, and epidemiologic evidence suggests that neurotoxic pesticides can also cause developmental neurotoxicity, and that the effects are more severe and lasting, and that they occur at much lower exposure levels. Some of this evidence relates to model substances that have now been banned or restricted, but currently used substances with similar mechanisms of toxicity should be regarded to share the same toxic potentials. Thus, many widely used pesticides, such as organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides should be considered neurodevelopmental toxicants, unless convincing evidence exists for individual substances that they deviate from the general group characteristics. Given the likely environmental aetiology of neurodevelopmental deficits and their importance to families and to society, prevention of exposures to neurotoxic pesticides should be made a public health priority. Existing uncertainties should not be used as an excuse for rejecting precautionary action.
ACh: Acetylcholine; AChE: Acetylcholinesterase; ADHD: Attention Deficit Hyperactivity Disorder; AMP: Adenosine monophosphate; ALS: Amyotrophic Lateral Sclerosis; CNS: Central Nervous System; CREB Ca2+/cAMP Response Element Binding protein; CT: Computed Tomography; 2,4-D: 2,4-Dichlorophenoxyacetic acid; DEDC: Diethyldithiocarbamate; EBDC: Ethylenebisdithiocarbamate; EEG: Electroencephalogram; ETU: Ethylenethiourea; EU: European Union; GABA: Gamma-aminobutyric acid; GSH: Glutathione; HSDB: Hazardous Substances Data Bank; IgG: Immunoglobulin G; mAChR: muscarinic acetylcholine receptor; MCPA: 4-chloro-2-methylphenoxyacetic acid; MDA: Malondialdehyde; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MRI: Magnetic Resonance Imaging; NADPH: Nicotinamide Adenine Dinucleotide Phosphate with a bound Hydrogen ion; NIOSH: National Institute of Occupational Safety and Health; NTE: Neuropathy Target Esterase; OECD: Organisation for Economic Co-operation and Development; OP: Organophosphate; OPIDP: OrganoPhosphate-Induced Delayed Polyneuropathy; PC12 cells: Cancer cell line from a pheochromocytoma of the rat adrenal medulla; ROS: Reactive Oxygen Species; Se-GPx: Selenium-glutathione peroxidase; SOD: Superoxide dismutase; 2,4,5-T: 2,4,5-trichlorophenoxyacetic acid; TH+: Tyrosine Hydroxylase immunopositive; TPX: Thyroid peroxidase.
Competing interests
PG is an editor of Environmental Health but was not involved in the editorial handling of this manuscript. The authors declare that they have no competing interests.
Authors' contributions
MBP, HRA and PG jointly conceived the review, MBP and HRA from mechanistic and toxicologic considerations and PG from an epidemiologic viewpoint. MBP conducted the literature survey and wrote the first draft, which all authors revised and updated. The final manuscript was approved by all authors.
Acknowledgements
This study was supported by a European Commission grant to the HENVINET project (Contract No. 037019 coordinated by the Norwegian Institute for Air Research). We thank Drs Gemma Calamandrei, Lilian Corra, Janna Koppe and Margaret Saunders for comments on an earlier draft of this manuscript.
  • The use of plant protection products in the European Union. Data 1992–2003. Eurostat statistical books http://epp.eurostat.ec.europa.eu/cache/ITY_OFFPUB/KS-76-06-669/EN/KS-76-06-669-EN.PDF
  • Monitoring of Pesticide Residues in Products of Plant Origin in the European Union, Norway, Iceland and Liechtenstein, 2005. Commision staff working document http://ec.europa.eu/food/fvo/specialreports/pesticide_residues/report_2005_en.pdf
  • Mage DT, Allen RH, Gondy G, Smith W, Barr DB, Needham LL. Estimating pesticide dose from urinary pesticide concentration data by creatinine correction in the Third National Health and Nutrition Examination Survey (NHANES-III) J Expo Anal Environ Epidemiol. 2004;14:457–465. doi: 10.1038/sj.jea.7500343. [PubMed] [Cross Ref]
  • Dobbing J. Vulnerable periods in developing brain. In: Davison AN, Dobbing J, editor. Applied Neurochemistry. Philadelphia: Davis; 1968. pp. 287–316.
  • Rodier PM. Developing brain as a target of toxicity. Environ Health Perspect. 1995;103:73–76. doi: 10.2307/3432351. [PMC free article] [PubMed] [Cross Ref]
  • Rice D, Barone S., Jr Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511–533. doi: 10.2307/3454543. [PMC free article] [PubMed] [Cross Ref]
  • Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong CE, Holland NT. Association between in utero organophosphate pesticide exposure and abnormal reflexes in neonates. Neurotoxicology. 2005;26:199–209. doi: 10.1016/j.neuro.2004.10.004. [PubMed] [Cross Ref]
  • Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect. 2007;115:792–798. [PMC free article] [PubMed]
  • Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS. Prenatal organophosphate metabolite and organochlorine levels and performance on the Brazelton Neonatal Behavioral Assessment Scale in a multiethnic pregnancy cohort. Am J Epidemiol. 2007;165:1397–1404. doi: 10.1093/aje/kwm029. [PubMed] [Cross Ref]
  • Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt RW. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics. 2006;118:e1845–e1859. doi: 10.1542/peds.2006-0338. [PMC free article] [PubMed] [Cross Ref]
  • Grandjean P, Harari R, Barr DB, Debes F. Pesticide exposure and stunting as independent predictors of neurobehavioral deficits in Ecuadorian school children. Pediatrics. 2006;117:e546–e556. doi: 10.1542/peds.2005-1781. [PubMed] [Cross Ref]
  • Ruckart PZ, Kakolewski K, Bove FJ, Kaye WE. Long-term neurobehavioral health effects of methyl parathion exposure in children in Mississippi and Ohio. Environ Health Perspect. 2004;112:46–51. [PMC free article] [PubMed]
  • Claudio L, Kwa WC, Russell AL, Wallinga D. Testing methods for developmental neurotoxicity of environmental chemicals. Toxicol Appl Pharmacol. 2000;164:1–14. doi: 10.1006/taap.2000.8890. [PubMed] [Cross Ref]
  • Eriksson P. Developmental neurotoxicity of environmental agents in the neonate. Neurotoxicology. 1997;18:719–726. [PubMed]
  • Tilson HA. The concern for developmental neurotoxicology: is it justified and what is being done about it? Environ Health Perspect. 1995;103:147–151. doi: 10.2307/3432365. [PMC free article] [PubMed] [Cross Ref]
  • Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. 2006;368:2167–2178. doi: 10.1016/S0140-6736(06)69665-7. [PubMed] [Cross Ref]
  • Schettler T. Toxic threats to neurologic development of children. Environ Health Perspect. 2001;109:813–816. doi: 10.2307/3454643. [PMC free article] [PubMed] [Cross Ref]
  • Boyle CA, Decoufle P, Yeargin-Allsopp M. Prevalence and health impact of developmental disabilities in US children. Pediatrics. 1994;93:399–403. [PubMed]
  • Landrigan PJ, Schechter CB, Lipton JM, Fahs MC, Schwartz J. Environmental pollutants and disease in American children: estimates of morbidity, mortality, and costs for lead poisoning, asthma, cancer, and developmental disabilities. Environ Health Perspect. 2002;110:721–728. [PMC free article] [PubMed]
  • Tilson HA. Neurotoxicology risk assessment guidelines: developmental neurotoxicology. Neurotoxicology. 2000;21:189–194. [PubMed]
  • Costa LG. Current issues in organophosphate toxicology. Clin Chim Acta. 2006;366:1–13. doi: 10.1016/j.cca.2005.10.008. [PubMed] [Cross Ref]
  • Lauder JM, Schambra UB. Morphogenetic roles of acetylcholine. Environ Health Perspect. 1999;107:65–69. doi: 10.2307/3434473. [PMC free article] [PubMed] [Cross Ref]
  • Clegg DJ, van Gemert M. Determination of the reference dose for chlorpyrifos: proceedings of an expert panel. J Toxicol Environ Health B Crit Rev. 1999;2:211–255. doi: 10.1080/109374099281179. [PubMed] [Cross Ref]
  • Lotti M. Clinical Toxicology of Anticholinesterase Agents in Humans. In: Krieger RI, editor. Handbook of Pesticide Toxicology. 2. Vol. 2. San Diego: Academic Press; 2001. pp. 1043–1085.
  • Lotti M. The pathogenesis of organophosphate polyneuropathy. Crit Rev Toxicol. 1991;21:465–487. doi: 10.3109/10408449209089884. [PubMed] [Cross Ref]
  • Johnson MK, Glynn P. Neuropathy target esterase (NTE) and organophosphorus-induced delayed polyneuropathy (OPIDP): recent advances. Toxicol Lett. 1995;82–83:459–463. doi: 10.1016/0378-4274(95)03495-1. [PubMed] [Cross Ref]
  • Lotti M, Moretto A. Organophosphate-induced delayed polyneuropathy. Toxicol Rev. 2005;24:37–49. doi: 10.2165/00139709-200524010-00003. [PubMed] [Cross Ref]
  • Pope CN, Chakraborti TK, Chapman ML, Farrar JD. Long-term neurochemical and behavioral effects induced by acute chlorpyrifos treatment. Pharmacol Biochem Behav. 1992;42:251–256. doi: 10.1016/0091-3057(92)90523-I. [PubMed] [Cross Ref]
  • Sanchez-Santed F, Canadas F, Flores P, Lopez-Grancha M, Cardona D. Long-term functional neurotoxicity of paraoxon and chlorpyrifos: behavioural and pharmacological evidence. Neurotoxicol Teratol. 2004;26:305–317. doi: 10.1016/j.ntt.2003.10.008. [PubMed] [Cross Ref]
  • Rosenstock L, Keifer M, Daniell WE, McConnell R, Claypoole K. Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health Effects Study Group. Lancet. 1991;338:223–227. doi: 10.1016/0140-6736(91)90356-T. [PubMed] [Cross Ref]
  • Steenland K. Chronic neurological effects of organophosphate pesticides. BMJ. 1996;312:1312–1313. [PMC free article] [PubMed]
  • Kamel F, Hoppin JA. Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect. 2004;112:950–958. [PMC free article] [PubMed]
  • Jamal GA, Hansen S, Julu PO. Low level exposures to organophosphorus esters may cause neurotoxicity. Toxicology. 2002;181–182:23–33. doi: 10.1016/S0300-483X(02)00447-X. [PubMed] [Cross Ref]
  • Colosio C, Tiramani M, Maroni M. Neurobehavioral effects of pesticides: state of the art. Neurotoxicology. 2003;24:577–591. doi: 10.1016/S0161-813X(03)00055-X. [PubMed] [Cross Ref]
  • Rothlein J, Rohlman D, Lasarev M, Phillips J, Muniz J, McCauley L. Organophosphate pesticide exposure and neurobehavioral performance in agricultural and non-agricultural Hispanic workers. Environ Health Perspect. 2006;114:691–696. [PMC free article] [PubMed]
  • Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP. Neurologic symptoms in licensed pesticide applicators in the Agricultural Health Study. Hum Exp Toxicol. 2007;26:243–250. doi: 10.1177/0960327107070582. [PubMed] [Cross Ref]
  • Lauder JM. Roles for neurotransmitters in development: possible interaction with drugs during the fetal and neonatal periods. Prog Clin Biol Res. 1985;163C:375–380. [PubMed]
  • Whitaker-Azmitia PM. Role of serotonin and other neurotransmitter receptors in brain development: basis for developmental pharmacology. Pharmacol Rev. 1991;43:553–561. [PubMed]
  • Pope CN, Chakraborti TK. Dose-related inhibition of brain and plasma cholinesterase in neonatal and adult rats following sublethal organophosphate exposures. Toxicology. 1992;73:35–43. doi: 10.1016/0300-483X(92)90168-E. [PubMed] [Cross Ref]
  • Pope CN, Chakraborti TK, Chapman ML, Farrar JD, Arthun D. Comparison of in vivo cholinesterase inhibition in neonatal and adult rats by three organophosphorothioate insecticides. Toxicology. 1991;68:51–61. doi: 10.1016/0300-483X(91)90061-5. [PubMed] [Cross Ref]
  • Song X, Seidler FJ, Saleh JL, Zhang J, Padilla S, Slotkin TA. Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade. Toxicol Appl Pharmacol. 1997;145:158–174. doi: 10.1006/taap.1997.8171. [PubMed] [Cross Ref]
  • Slotkin TA. Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates. Toxicol Appl Pharmacol. 2004;198:132–151. doi: 10.1016/j.taap.2003.06.001. [PubMed] [Cross Ref]
  • Dam K, Seidler FJ, Slotkin TA. Chlorpyrifos exposure during a critical neonatal period elicits gender-selective deficits in the development of coordination skills and locomotor activity. Brain Res Dev Brain Res. 2000;121:179–187. doi: 10.1016/S0165-3806(00)00044-4. [PubMed] [Cross Ref]
  • Ricceri L, Markina N, Valanzano A, Fortuna S, Cometa MF, Meneguz A, Calamandrei G. Developmental exposure to chlorpyrifos alters reactivity to environmental and social cues in adolescent mice. Toxicol Appl Pharmacol. 2003;191:189–201. doi: 10.1016/S0041-008X(03)00229-1. [PubMed] [Cross Ref]
  • Icenogle LM, Christopher NC, Blackwelder WP, Caldwell DP, Qiao D, Seidler FJ, Slotkin TA, Levin ED. Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation. Neurotoxicol Teratol. 2004;26:95–101. doi: 10.1016/j.ntt.2003.09.001. [PubMed] [Cross Ref]
  • Ricceri L, Venerosi A, Capone F, Cometa MF, Lorenzini P, Fortuna S, Calamandrei G. Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice. Toxicol Sci. 2006;93:105–113. doi: 10.1093/toxsci/kfl032. [PubMed] [Cross Ref]
  • Ostrea EM, Morales V, Ngoumgna E, Prescilla R, Tan E, Hernandez E, Ramirez GB, Cifra HL, Manlapaz ML. Prevalence of fetal exposure to environmental toxins as determined by meconium analysis. Neurotoxicology. 2002;23:329–339. doi: 10.1016/S0161-813X(02)00077-3. [PubMed] [Cross Ref]
  • Roy TS, Andrews JE, Seidler FJ, Slotkin TA. Chlorpyrifos elicits mitotic abnormalities and apoptosis in neuroepithelium of cultured rat embryos. Teratology. 1998;58:62–68. doi: 10.1002/(SICI)1096-9926(199808)58:2<62::AID-TERA7>3.0.CO;2-2. [PubMed] [Cross Ref]
  • Qiao D, Seidler FJ, Padilla S, Slotkin TA. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period? Environ Health Perspect. 2002;110:1097–1103. [PMC free article] [PubMed]
  • Qiao D, Seidler FJ, Abreu-Villaca Y, Tate CA, Cousins MM, Slotkin TA. Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood. Brain Res Dev Brain Res. 2004;148:43–52. doi: 10.1016/j.devbrainres.2003.10.004. [PubMed] [Cross Ref]
  • Qiao D, Seidler FJ, Tate CA, Cousins MM, Slotkin TA. Fetal chlorpyrifos exposure: adverse effects on brain cell development and cholinergic biomarkers emerge postnatally and continue into adolescence and adulthood. Environ Health Perspect. 2003;111:536–544. [PMC free article] [PubMed]
  • Levin ED, Addy N, Nakajima A, Christopher NC, Seidler FJ, Slotkin TA. Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats. Brain Res Dev Brain Res. 2001;130:83–89. doi: 10.1016/S0165-3806(01)00215-2. [PubMed] [Cross Ref]
  • Moser VC. Dose-response and time-course of neurobehavioral changes following oral chlorpyrifos in rats of different ages. Neurotoxicol Teratol. 2000;22:713–723. doi: 10.1016/S0892-0362(00)00087-8. [PubMed] [Cross Ref]
  • Vidair CA. Age dependence of organophosphate and carbamate neurotoxicity in the postnatal rat: extrapolation to the human. Toxicol Appl Pharmacol. 2004;196:287–302. doi: 10.1016/j.taap.2003.12.016. [PubMed] [Cross Ref]
  • Garcia SJ, Seidler FJ, Crumpton TL, Slotkin TA. Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells. Brain Res. 2001;891:54–68. doi: 10.1016/S0006-8993(00)03189-9. [PubMed] [Cross Ref]
  • Garcia SJ, Seidler FJ, Qiao D, Slotkin TA. Chlorpyrifos targets developing glia: effects on glial fibrillary acidic protein. Brain Res Dev Brain Res. 2002;133:151–161. doi: 10.1016/S0165-3806(02)00283-3. [PubMed] [Cross Ref]
  • Qiao D, Seidler FJ, Slotkin TA. Developmental neurotoxicity of chlorpyrifos modeled in vitro: comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesis in PC12 and C6 cells. Environ Health Perspect. 2001;109:909–913. doi: 10.2307/3454991. [PMC free article] [PubMed] [Cross Ref]
  • Slotkin TA, Seidler FJ. Comparative developmental neurotoxicity of organophosphates in vivo: transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems. Brain Res Bull. 2007;72:232–274. doi: 10.1016/j.brainresbull.2007.01.005. [PMC free article] [PubMed] [Cross Ref]
  • Slotkin TA, Seidler FJ, Fumagalli F. Exposure to organophosphates reduces the expression of neurotrophic factors in neonatal rat brain regions: similarities and differences in the effects of chlorpyrifos and diazinon on the fibroblast growth factor superfamily. Environ Health Perspect. 2007;115:909–916. [PMC free article] [PubMed]
  • Slotkin TA, Bodwell BE, Levin ED, Seidler FJ. Neonatal exposure to low doses of diazinon: long-term effects on neural cell development and acetylcholine systems. Environ Health Perspect. 2008;116:340–348. [PMC free article] [PubMed]
  • Berkowitz GS, Wetmur JG, Birman-Deych E, Obel J, Lapinski RH, Godbold JH, Holzman IR, Wolff MS. In utero pesticide exposure, maternal paraoxonase activity, and head circumference. Environ Health Perspect. 2004;112:388–391. [PMC free article] [PubMed]
  • Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, Hoepner LA, Diaz D, Dietrich J, Reyes A, Tang D, Kinney PL, Perera FP. Prenatal insecticide exposures and birth weight and length among an urban minority cohort. Environ Health Perspect. 2004;112:1125–1132. [PMC free article] [PubMed]
  • Barr DB, Allen R, Olsson AO, Bravo R, Caltabiano LM, Montesano A, Nguyen J, Udunka S, Walden D, Walker RD, Weerasekera G, Whitehead RD, Jr, Schober SE, Needham LL. Concentrations of selective metabolites of organophosphorus pesticides in the United States population. Environ Res. 2005;99:314–326. doi: 10.1016/j.envres.2005.03.012. [PubMed] [Cross Ref]
  • Aprea C, Strambi M, Novelli MT, Lunghini L, Bozzi N. Biologic monitoring of exposure to organophosphorus pesticides in 195 Italian children. Environ Health Perspect. 2000;108:521–525. doi: 10.2307/3454613. [PMC free article] [PubMed] [Cross Ref]
  • Heudorf U, Butte W, Schulz C, Angerer J. Reference values for metabolites of pyrethroid and organophosphorous insecticides in urine for human biomonitoring in environmental medicine. Int J Hyg Environ Health. 2006;209:293–299. doi: 10.1016/j.ijheh.2006.01.001. [PubMed] [Cross Ref]
  • Ye X, Pierik FH, Hauser R, Duty S, Angerer J, Park MM, Burdorf A, Hofman A, Jaddoe VW, Mackenbach JP, Steegers EA, Tiemeier H, Longnecker MP. Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: The Generation R study. Environ Res. 2008;108:260–267. doi: 10.1016/j.envres.2008.07.014. [PMC free article] [PubMed] [Cross Ref]
  • Ecobichon DJ. Carbamate Insecticides. In: Krieger RI, editor. Handbook of Pesticide Toxicology. 2. Vol. 2. San Diego: Academic Press; 2001. pp. 1087–1106.
  • Lifshitz M, Shahak E, Bolotin A, Sofer S. Carbamate poisoning in early childhood and in adults. J Toxicol Clin Toxicol. 1997;35:25–27. [PubMed]
  • Lifshitz M, Shahak E, Sofer S. Carbamate and organophosphate poisoning in young children. Pediatr Emerg Care. 1999;15:102–103. doi: 10.1097/00006565-199904000-00006. [PubMed] [Cross Ref]
  • Kamboj A, Kiran R, Sandhir R. Carbofuran-induced neurochemical and neurobehavioral alterations in rats: attenuation by N-acetylcysteine. Exp Brain Res. 2006;170:567–575. doi: 10.1007/s00221-005-0241-5. [PubMed] [Cross Ref]
  • Gupta RC, Milatovic S, Dettbarn WD, Aschner M, Milatovic D. Neuronal oxidative injury and dendritic damage induced by carbofuran: protection by memantine. Toxicol Appl Pharmacol. 2007;219:97–105. doi: 10.1016/j.taap.2006.10.028. [PubMed] [Cross Ref]
  • Roldan-Tapi L, Leyva A, Laynez F, Santed FS. Chronic neuropsychological sequelae of cholinesterase inhibitors in the absence of structural brain damage: two cases of acute poisoning. Environ Health Perspect. 2005;113:762–766. [PMC free article] [PubMed]
  • Slotkin TA, Mackillop EA, Ryde IT, Tate CA, Seidler FJ. Screening for developmental neurotoxicity using PC12 cells: comparisons of organophosphates with a carbamate, an organochlorine, and divalent nickel. Environ Health Perspect. 2007;115:93–101. [PMC free article] [PubMed]
  • Casida JE. Pyrethrum flowers and pyrethroid insecticides. Environ Health Perspect. 1980;34:189–202. doi: 10.2307/3428960. [PMC free article] [PubMed] [Cross Ref]
  • Shafer TJ, Meyer DA, Crofton KM. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environ Health Perspect. 2005;113:123–136. [PMC free article] [PubMed]
  • Ray DE, Fry JR. A reassessment of the neurotoxicity of pyrethroid insecticides. Pharmacol Ther. 2006;111:174–193. doi: 10.1016/j.pharmthera.2005.10.003. [PubMed] [Cross Ref]
  • Bradberry SM, Cage SA, Proudfoot AT, Vale JA. Poisoning due to pyrethroids. Toxicol Rev. 2005;24:93–106. doi: 10.2165/00139709-200524020-00003. [PubMed] [Cross Ref]
  • He F, Wang S, Liu L, Chen S, Zhang Z, Sun J. Clinical manifestations and diagnosis of acute pyrethroid poisoning. Arch Toxicol. 1989;63:54–58. doi: 10.1007/BF00334635. [PubMed] [Cross Ref]
  • Chen SY, Zhang ZW, He FS, Yao PP, Wu YQ, Sun JX, Liu LH, Li QG. An epidemiological study on occupational acute pyrethroid poisoning in cotton farmers. Br J Ind Med. 1991;48:77–81. [PMC free article] [PubMed]
  • Sheets LP, Doherty JD, Law MW, Reiter LW, Crofton KM. Age-dependent differences in the susceptibility of rats to deltamethrin. Toxicol Appl Pharmacol. 1994;126:186–190. doi: 10.1006/taap.1994.1106. [PubMed] [Cross Ref]
  • Cantalamessa F. Acute toxicity of two pyrethroids, permethrin, and cypermethrin in neonatal and adult rats. Arch Toxicol. 1993;67:510–513. doi: 10.1007/BF01969923. [PubMed] [Cross Ref]
  • Sheets LP. A consideration of age-dependent differences in susceptibility to organophosphorus and pyrethroid insecticides. Neurotoxicology. 2000;21:57–63. [PubMed]
  • Meisler MH, Kearney J, Ottman R, Escayg A. Identification of epilepsy genes in human and mouse. Annu Rev Genet. 2001;35:567–588. doi: 10.1146/annurev.genet.35.102401.091142. [PMC free article] [PubMed] [Cross Ref]
  • Adams J, Vorhees CV, Middaugh LD. Developmental neurotoxicity of anticonvulsants: human and animal evidence on phenytoin. Neurotoxicol Teratol. 1990;12:203–214. doi: 10.1016/0892-0362(90)90092-Q. [PubMed] [Cross Ref]
  • Ahlbom J, Fredriksson A, Eriksson P. Neonatal exposure to a type-I pyrethroid (bioallethrin) induces dose-response changes in brain muscarinic receptors and behaviour in neonatal and adult mice. Brain Res. 1994;645:318–324. doi: 10.1016/0006-8993(94)91666-7. [PubMed] [Cross Ref]
  • Eriksson P, Fredriksson A. Neurotoxic effects of two different pyrethroids, bioallethrin and deltamethrin, on immature and adult mice: changes in behavioral and muscarinic receptor variables. Toxicol Appl Pharmacol. 1991;108:78–85. doi: 10.1016/0041-008X(91)90270-O. [PubMed] [Cross Ref]
  • Eriksson P, Nordberg A. Effects of two pyrethroids, bioallethrin and deltamethrin, on subpopulations of muscarinic and nicotinic receptors in the neonatal mouse brain. Toxicol Appl Pharmacol. 1990;102:456–463. doi: 10.1016/0041-008X(90)90041-R. [PubMed] [Cross Ref]
  • Talts U, Fredriksson A, Eriksson P. Changes in behavior and muscarinic receptor density after neonatal and adult exposure to bioallethrin. Neurobiol Aging. 1998;19:545–552. doi: 10.1016/S0197-4580(98)00093-1. [PubMed] [Cross Ref]
  • Moniz AC, Bernardi MM, Souza-Spinosa HS, Palermo-Neto J. Effects of exposure to a pyrethroid insecticide during lactation on the behavior of infant and adult rats. Braz J Med Biol Res. 1990;23:45–48. [PubMed]
  • Husain R, Malaviya M, Seth PK, Husain R. Differential responses of regional brain polyamines following in utero exposure to synthetic pyrethroid insecticides: a preliminary report. Bull Environ Contam Toxicol. 1992;49:402–409. doi: 10.1007/BF01239644. [PubMed] [Cross Ref]
  • Lazarini CA, Florio JC, Lemonica IP, Bernardi MM. Effects of prenatal exposure to deltamethrin on forced swimming behavior, motor activity, and striatal dopamine levels in male and female rats. Neurotoxicol Teratol. 2001;23:665–673. doi: 10.1016/S0892-0362(01)00170-2. [PubMed] [Cross Ref]
  • Aziz MH, Agrawal AK, Adhami VM, Shukla Y, Seth PK. Neurodevelopmental consequences of gestational exposure (GD14-GD20) to low dose deltamethrin in rats. Neurosci Lett. 2001;300:161–165. doi: 10.1016/S0304-3940(01)01543-9. [PubMed] [Cross Ref]
  • Malaviya M, Husain R, Seth PK, Husain R. Perinatal effects of two pyrethroid insecticides on brain neurotransmitter function in the neonatal rat. Vet Hum Toxicol. 1993;35:119–122. [PubMed]
  • Gupta A, Agarwal R, Shukla GS. Functional impairment of blood-brain barrier following pesticide exposure during early development in rats. Hum Exp Toxicol. 1999;18:174–179. doi: 10.1191/096032799678839860. [PubMed] [Cross Ref]
  • Nasuti C, Gabbianelli R, Falcioni ML, Di SA, Sozio P, Cantalamessa F. Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids. Toxicology. 2007;229:194–205. doi: 10.1016/j.tox.2006.10.015. [PubMed] [Cross Ref]
  • Farag AT, Goda NF, Mansee AH, Shaaban NA. Effects of permethrin given before mating on the behavior of F1-generation in mice. Neurotoxicology. 2006;27:421–428. doi: 10.1016/j.neuro.2005.12.001. [PubMed] [Cross Ref]
  • Tran V, Hoffman N, Mofunanaya A, Pryor SC, Ojugbele O, McLaughlin A, Gibson L, Bonventre JA, Flynn K, Weeks BS. Bifenthrin inhibits neurite outgrowth in differentiating PC12 cells. Med Sci Monit. 2006;12:BR57–BR62. [PubMed]
  • Schettgen T, Heudorf U, Drexler H, Angerer J. Pyrethroid exposure of the general population-is this due to diet. Toxicol Lett. 2002;134:141–145. doi: 10.1016/S0378-4274(02)00183-2. [PubMed] [Cross Ref]
  • Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, Landrigan PJ, Wolff MS. Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort. Environ Health Perspect. 2003;111:79–84. [PMC free article] [PubMed]
  • Heudorf U, Angerer J, Drexler H. Current internal exposure to pesticides in children and adolescents in Germany: urinary levels of metabolites of pyrethroid and organophosphorus insecticides. Int Arch Occup Environ Health. 2004;77:67–72. doi: 10.1007/s00420-003-0470-5. [PubMed] [Cross Ref]
  • Miller DB. Neurotoxicity of the pesticidal carbamates. Neurobehav Toxicol Teratol. 1982;4:779–787. [PubMed]
  • Schmuck G, Ahr HJ, Mihail F, Stahl B, Kayser M. Effects of the dithiocarbamate fungicide propineb in primary neuronal cell cultures and skeletal muscle cells of the rat. Arch Toxicol. 2002;76:414–422. doi: 10.1007/s00204-002-0353-7. [PubMed] [Cross Ref]
  • Lee CC, Peters PJ. Neurotoxicity and behavioral effects of thiram in rats. Environ Health Perspect. 1976;17:35–43. doi: 10.2307/3428607. [PMC free article] [PubMed] [Cross Ref]
  • Vaccari A, Ferraro L, Saba P, Ruiu S, Mocci I, Antonelli T, Tanganelli S. Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate. J Pharmacol Exp Ther. 1998;285:961–967. [PubMed]
  • Delmaestro E, Trombetta LD. The effects of disulfiram on the hippocampus and cerebellum of the rat brain: a study on oxidative stress. Toxicol Lett. 1995;75:235–243. doi: 10.1016/0378-4274(94)03187-C. [PubMed] [Cross Ref]
  • Orrenius S, Nobel CS, Dobbelsteen DJ van den, Burkitt MJ, Slater AF. Dithiocarbamates and the redox regulation of cell death. Biochem Soc Trans. 1996;24:1032–1038. [PubMed]
  • Heikkila RE, Cabbat FS, Cohen G. In vivo inhibition of superoxide dismutase in mice by diethyldithiocarbamate. J Biol Chem. 1976;251:2182–2185. [PubMed]
  • Zhang J, Fitsanakis VA, Gu G, Jing D, Ao M, Amarnath V, Montine TJ. Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. J Neurochem. 2003;84:336–346. doi: 10.1046/j.1471-4159.2003.01525.x. [PubMed] [Cross Ref]
  • Domico LM, Zeevalk GD, Bernard LP, Cooper KR. Acute neurotoxic effects of mancozeb and maneb in mesencephalic neuronal cultures are associated with mitochondrial dysfunction. Neurotoxicology. 2006;27:816–825. doi: 10.1016/j.neuro.2006.07.009. [PubMed] [Cross Ref]
  • Domico LM, Cooper KR, Bernard LP, Zeevalk GD. Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells. Neurotoxicology. 2007;28:1079–1091. doi: 10.1016/j.neuro.2007.04.008. [PMC free article] [PubMed] [Cross Ref]
  • Doerge DR, Takazawa RS. Mechanism of thyroid peroxidase inhibition by ethylenethiourea. Chem Res Toxicol. 1990;3:98–101. doi: 10.1021/tx00014a003. [PubMed] [Cross Ref]
  • Marinovich M, Guizzetti M, Ghilardi F, Viviani B, Corsini E, Galli CL. Thyroid peroxidase as toxicity target for dithiocarbamates. Arch Toxicol. 1997;71:508–512. doi: 10.1007/s002040050420. [PubMed] [Cross Ref]
  • Vaccari A, Saba P, Mocci I, Ruiu S. Dithiocarbamate pesticides affect glutamate transport in brain synaptic vesicles. J Pharmacol Exp Ther. 1999;288:1–5. [PubMed]
  • Liesivuori J, Savolainen K. Dithiocarbamates. Toxicology. 1994;91:37–42. doi: 10.1016/0300-483X(94)90238-0. [PubMed] [Cross Ref]
  • Hoogenraad TU. Dithiocarbamates and Parkinson's disease. Lancet. 1988;1:767. doi: 10.1016/S0140-6736(88)91573-5. [PubMed] [Cross Ref]
  • Debbarh I, Rambelomanana S, Penouil F, Castaigne F, Poisot D, Moore N. [Human neurotoxicity of ethylene-bis-dithiocarbamates (EBDC)] Rev Neurol (Paris) 2002;158:1175–1180. [PubMed]
  • Ferraz HB, Bertolucci PH, Pereira JS, Lima JG, Andrade LA. Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology. 1988;38:550–553. [PubMed]
  • Meco G, Bonifati V, Vanacore N, Fabrizio E. Parkinsonism after chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate) Scand J Work Environ Health. 1994;20:301–305. [PubMed]
  • Barlow BK, Lee DW, Cory-Slechta DA, Opanashuk LA. Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells. Neurotoxicology. 2005;26:63–75. doi: 10.1016/j.neuro.2004.07.004. [PubMed] [Cross Ref]
  • Zhou Y, Shie FS, Piccardo P, Montine TJ, Zhang J. Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: relevance to Parkinson's disease. Neuroscience. 2004;128:281–291. doi: 10.1016/j.neuroscience.2004.06.048. [PubMed] [Cross Ref]
  • Fitsanakis VA, Amarnath V, Moore JT, Montine KS, Zhang J, Montine TJ. Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides. Free Radic Biol Med. 2002;33:1714–1723. doi: 10.1016/S0891-5849(02)01169-3. [PubMed] [Cross Ref]
  • Takahashi RN, Rogerio R, Zanin M. Maneb enhances MPTP neurotoxicity in mice. Res Commun Chem Pathol Pharmacol. 1989;66:167–170. [PubMed]
  • Bachurin SO, Shevtzova EP, Lermontova NN, Serkova TP, Ramsay RR. The effect of dithiocarbamates on neurotoxic action of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on mitochondrial respiration chain. Neurotoxicology. 1996;17:897–903. [PubMed]
  • McGrew DM, Irwin I, Langston JW. Ethylenebisdithiocarbamate enhances MPTP-induced striatal dopamine depletion in mice. Neurotoxicology. 2000;21:309–312. [PubMed]
  • Sook HM, Shin KJ, Kim YH, Kim SH, Lee T, Kim E, Ho RS, Suh PG. Thiram and ziram stimulate non-selective cation channel and induce apoptosis in PC12 cells. Neurotoxicology. 2003;24:425–434. doi: 10.1016/S0161-813X(03)00013-5. [PubMed] [Cross Ref]
  • Hurt S, Ollinger J, Arce G, Bui Q, Tobia AJ, van Ravenswaay B. Dialkyldithiocarbamates. In: Krieger RI, editor. Handbook of Pesticide Toxicology. 2. Vol. 2. San Diego: Academic Press; 2001. pp. 1759–1779.
  • Cooper RL, Kavlock RJ. Endocrine disruptors and reproductive development: a weight-of-evidence overview. J Endocrinol. 1997;152:159–166. doi: 10.1677/joe.0.1520159. [PubMed] [Cross Ref]
  • Colborn T. Neurodevelopment and endocrine disruption. Environ Health Perspect. 2004;112:944–949. [PMC free article] [PubMed]
  • Andersson M, de Benoist B, Delange F, Zupan J. Prevention and control of iodine deficiency in pregnant and lactating women and in children less than 2-years-old: conclusions and recommendations of the Technical Consultation. Public Health Nutr. 2007;10:1606–1611. doi: 10.1017/S1368980007000092. [PubMed] [Cross Ref]
  • Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O'Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341:549–555. doi: 10.1056/NEJM199908193410801. [PubMed] [Cross Ref]
  • Howdeshell KL. A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect. 2002;110:337–348. [PMC free article] [PubMed]
  • Cory-Slechta DA, Thiruchelvam M, Richfield EK, Barlow BK, Brooks AI. Developmental pesticide exposures and the Parkinson's disease phenotype. Birth Defects Res A Clin Mol Teratol. 2005;73:136–139. doi: 10.1002/bdra.20118. [PubMed] [Cross Ref]
  • Charles JM, Cunny HC, Wilson RD, Bus JS. Comparative subchronic studies on 2,4-dichlorophenoxyacetic acid, amine, and ester in rats. Fundam Appl Toxicol. 1996;33:161–165. doi: 10.1006/faat.1996.0153. [PubMed] [Cross Ref]
  • Rosso SB, Gonzalez M, Bagatolli LA, Duffard RO, Fidelio GD. Evidence of a strong interaction of 2,4-dichlorophenoxyacetic acid herbicide with human serum albumin. Life Sci. 1998;63:2343–2351. doi: 10.1016/S0024-3205(98)00523-2. [PubMed] [Cross Ref]
  • Bradberry SM, Watt BE, Proudfoot AT, Vale JA. Mechanisms of toxicity, clinical features, and management of acute chlorophenoxy herbicide poisoning: a review. J Toxicol Clin Toxicol. 2000;38:111–122. doi: 10.1081/CLT-100100925. [PubMed] [Cross Ref]
  • Suwalsky M, Benites M, Villena F, Aguilar F, Sotomayor CP. Interaction of 2,4-dichlorophenoxyacetic acid (2,4-D) with cell and model membranes. Biochim Biophys Acta. 1996;1285:267–276. doi: 10.1016/S0005-2736(96)00173-3. [PubMed] [Cross Ref]
  • Elo H, Ylitalo P. Substantial increase in the levels of chlorophenoxyacetic acids in the CNS of rats as a result of severe intoxication. Acta Pharmacol Toxicol (Copenh) 1977;41:280–284. [PubMed]
  • Elo HA, Ylitalo P. Distribution of 2-methyl-4-chlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid in male rats: evidence for the involvement of the central nervous system in their toxicity. Toxicol Appl Pharmacol. 1979;51:439–446. doi: 10.1016/0041-008X(79)90368-5. [PubMed] [Cross Ref]
  • Kim CS, Keizer RF, Pritchard JB. 2,4-Dichlorophenoxyacetic acid intoxication increases its accumulation within the brain. Brain Res. 1988;440:216–226. doi: 10.1016/0006-8993(88)90989-4. [PubMed] [Cross Ref]
  • Hervonen H, Elo HA, Ylitalo P. Blood-brain barrier damage by 2-methyl-4-chlorophenoxyacetic acid herbicide in rats. Toxicol Appl Pharmacol. 1982;65:23–31. doi: 10.1016/0041-008X(82)90358-1. [PubMed] [Cross Ref]
  • Elo HA, Hervonen H, Ylitalo P. Comparative study on cerebrovascular injuries by three chlorophenoxyacetic acids (2,4-D, 2,4,5-T and MCPA) Comp Biochem Physiol C. 1988;90:65–68. doi: 10.1016/0742-8413(88)90098-9. [PubMed] [Cross Ref]
  • Kim CS, Pritchard JB. Transport of 2,4,5-trichlorophenoxyacetic acid across the blood-cerebrospinal fluid barrier of the rabbit. J Pharmacol Exp Ther. 1993;267:751–757. [PubMed]
  • Kim CS, Keizer RF, Ambrose WW, Breese GR. Effects of 2,4,5-trichlorophenoxyacetic acid and quinolinic acid on 5-hydroxy-3-indoleacetic acid transport by the rabbit choroid plexus: pharmacology and electron microscopic cytochemistry. Toxicol Appl Pharmacol. 1987;90:436–444. doi: 10.1016/0041-008X(87)90136-0. [PubMed] [Cross Ref]
  • Elo HA, MacDonald E. Effects of 2,4-dichlorophenoxyacetic acid (2,4-D) on biogenic amines and their acidic metabolites in brain and cerebrospinal fluid of rats. Arch Toxicol. 1989;63:127–130. doi: 10.1007/BF00316434. [PubMed] [Cross Ref]
  • Bongiovanni B, De LP, Ferri A, Konjuh C, Rassetto M, Evangelista de Duffard AM, Cardinali DP, Duffard R. Melatonin decreases the oxidative stress produced by 2,4-dichlorophenoxyacetic acid in rat cerebellar granule cells. Neurotox Res. 2007;11:93–99. [PubMed]
  • Rosso SB, Caceres AO, de Duffard AM, Duffard RO, Quiroga S. 2,4-Dichlorophenoxyacetic acid disrupts the cytoskeleton and disorganizes the Golgi apparatus of cultured neurons. Toxicol Sci. 2000;56:133–140. doi: 10.1093/toxsci/56.1.133. [PubMed] [Cross Ref]
  • De Moliner KL, Evangelista de Duffard AM, Soto E, Duffard R, Adamo AM. Induction of apoptosis in cerebellar granule cells by 2,4-dichlorophenoxyacetic acid. Neurochem Res. 2002;27:1439–1446. doi: 10.1023/A:1021665720446. [PubMed] [Cross Ref]
  • Garabrant DH, Philbert MA. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) epidemiology and toxicology. Crit Rev Toxicol. 2002;32:233–257. doi: 10.1080/20024091064237. [PubMed] [Cross Ref]
  • Burns CJ, Beard KK, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945–94: an update. Occup Environ Med. 2001;58:24–30. doi: 10.1136/oem.58.1.24. [PMC free article] [PubMed] [Cross Ref]
  • Casey PH, Collie WR. Severe mental retardation and multiple congenital anomalies of uncertain cause after extreme parental exposure to 2,4-D. J Pediatr. 1984;104:313–315. doi: 10.1016/S0022-3476(84)81022-7. [PubMed] [Cross Ref]
  • Mori de Moro G, Duffard R, Evangelista de Duffard AM. Neurotoxicity of 2,4-dichlorophenoxyacetic butyl ester in chick embryos. Neurochem Res. 1993;18:353–359. doi: 10.1007/BF00969095. [PubMed] [Cross Ref]
  • Duffard R, Garcia G, Rosso S, Bortolozzi A, Madariaga M, di PO, Evangelista de Duffard AM. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacetic acid throughout lactation. Neurotoxicol Teratol. 1996;18:691–696. doi: 10.1016/S0892-0362(96)00087-6. [PubMed] [Cross Ref]
  • Rosso SB, Di Paolo OA, Evangelista de Duffard AM, Duffard R. Effects of 2,4-dichlorophenoxyacetic acid on central nervous system of developmental rats. Associated changes in ganglioside pattern. Brain Res. 1997;769:163–167. doi: 10.1016/S0006-8993(97)00823-8. [PubMed] [Cross Ref]
  • Evangelista de Duffard AM, Brusco A, Duffard R, Garcia G, Pecci SJ. Changes in serotonin-immunoreactivity in the dorsal and median raphe nuclei of rats exposed to 2,4-dichlorophenoxyacetic acid through lactation. Mol Chem Neuropathol. 1995;26:187–193. [PubMed]
  • Ferri A, Duffard R, de Duffard AM. Selective oxidative stress in brain areas of neonate rats exposed to 2,4-Dichlorophenoxyacetic acid through mother's milk. Drug Chem Toxicol. 2007;30:17–30. doi: 10.1080/01480540601017629. [PubMed] [Cross Ref]
  • Bortolozzi AA, Duffard RO, Evangelista de Duffard AM. Behavioral alterations induced in rats by a pre- and postnatal exposure to 2,4-dichlorophenoxyacetic acid. Neurotoxicol Teratol. 1999;21:451–465. doi: 10.1016/S0892-0362(98)00059-2. [PubMed] [Cross Ref]
  • Bortolozzi AA, Evangelista de Duffard AM, Duffard RO, Antonelli MC. Effects of 2,4-dichlorophenoxyacetic acid exposure on dopamine D2-like receptors in rat brain. Neurotoxicol Teratol. 2004;26:599–605. doi: 10.1016/j.ntt.2004.04.001. [PubMed] [Cross Ref]
  • Clark DG, McElligott TF, Hurst EW. The toxicity of paraquat. Br J Ind Med. 1966;23:126–132. [PMC free article] [PubMed]
  • Smith LL. Mechanism of paraquat toxicity in lung and its relevance to treatment. Hum Toxicol. 1987;6:31–36. [PubMed]
  • Jones GM, Vale JA. Mechanisms of toxicity, clinical features, and management of diquat poisoning: a review. J Toxicol Clin Toxicol. 2000;38:123–128. doi: 10.1081/CLT-100100926. [PubMed] [Cross Ref]
  • Saeed SA, Wilks MF, Coupe M. Acute diquat poisoning with intracerebral bleeding. Postgrad Med J. 2001;77:329–332. doi: 10.1136/pmj.77.907.329. [PMC free article] [PubMed] [Cross Ref]
  • Alcaro S, Arcone R, Vecchio I, Ortuso F, Gallelli A, Pasceri R, Procopio A, Iannone M. Molecular modelling and enzymatic studies of acetylcholinesterase and butyrylcholinesterase recognition with paraquat and related compounds. SAR QSAR Environ Res. 2007;18:595–602. doi: 10.1080/10629360701428433. [PubMed] [Cross Ref]
  • Vanholder R, Colardyn F, De RJ, Praet M, Lameire N, Ringoir S. Diquat intoxication: report of two cases and review of the literature. Am J Med. 1981;70:1267–1271. doi: 10.1016/0002-9343(81)90836-6. [PubMed] [Cross Ref]
  • McCarthy LG, Speth CP. Diquat intoxication. Ann Emerg Med. 1983;12:394–396. doi: 10.1016/S0196-0644(83)80474-0. [PubMed] [Cross Ref]
  • Schmidt DM, Neale J, Olson KR. Clinical course of a fatal ingestion of diquat. J Toxicol Clin Toxicol. 1999;37:881–884. doi: 10.1081/CLT-100102471. [PubMed] [Cross Ref]
  • Rudez J, Sepcic K, Sepcic J. Vaginally applied diquat intoxication. J Toxicol Clin Toxicol. 1999;37:877–879. doi: 10.1081/CLT-100102470. [PubMed] [Cross Ref]
  • Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC. Environmental risk factors and Parkinson's disease: a case-control study in Taiwan. Neurology. 1997;48:1583–1588. [PubMed]
  • McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA. Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10:119–127. doi: 10.1006/nbdi.2002.0507. [PubMed] [Cross Ref]
  • Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA. Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci. 2003;23:3095–3099. [PubMed]
  • Sechi GP, Agnetti V, Piredda M, Canu M, Deserra F, Omar HA, Rosati G. Acute and persistent parkinsonism after use of diquat. Neurology. 1992;42:261–263. [PubMed]
  • McCormack AL, Atienza JG, Johnston LC, Andersen JK, Vu S, Di Monte DA. Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J Neurochem. 2005;93:1030–1037. doi: 10.1111/j.1471-4159.2005.03088.x. [PubMed] [Cross Ref]
  • Di Monte DA. The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol. 2003;2:531–538. doi: 10.1016/S1474-4422(03)00501-5. [PubMed] [Cross Ref]
  • Bharath S, Hsu M, Kaur D, Rajagopalan S, Andersen JK. Glutathione, iron and Parkinson's disease. Biochem Pharmacol. 2002;64:1037–1048. doi: 10.1016/S0006-2952(02)01174-7. [PubMed] [Cross Ref]
  • Fredriksson A, Fredriksson M, Eriksson P. Neonatal exposure to paraquat or MPTP induces permanent changes in striatum dopamine and behavior in adult mice. Toxicol Appl Pharmacol. 1993;122:258–264. doi: 10.1006/taap.1993.1194. [PubMed] [Cross Ref]
  • Barlow BK, Richfield EK, Cory-Slechta DA, Thiruchelvam M. A fetal risk factor for Parkinson's disease. Dev Neurosci. 2004;26:11–23. doi: 10.1159/000080707. [PubMed] [Cross Ref]
  • Dua R, Gill KD. Effect of aluminium phosphide exposure on kinetic properties of cytochrome oxidase and mitochondrial energy metabolism in rat brain. Biochim Biophys Acta. 2004;1674:4–11. [PubMed]
  • Price NR, Chambers J. Biochemistry of Phosphines. In: Hartley FR, editor. The Chemistry of Organophosphorus Compounds. Vol. 1. London: Wiley; 1990. pp. 643–661.
  • Bolter CJ, Chefurka W. Extramitochondrial release of hydrogen peroxide from insect and mouse liver mitochondria using the respiratory inhibitors phosphine, myxothiazol, and antimycin and spectral analysis of inhibited cytochromes. Arch Biochem Biophys. 1990;278:65–72. doi: 10.1016/0003-9861(90)90232-N. [PubMed] [Cross Ref]
  • Price NR, Dance SJ. Some biochemical aspects of phosphine action and resistance in three species of stored product beetles. Comp Biochem Physiol C. 1983;76:277–281. doi: 10.1016/0742-8413(83)90078-6. [PubMed] [Cross Ref]
  • Dua R, Gill KD. Aluminium phosphide exposure: implications on rat brain lipid peroxidation and antioxidant defence system. Pharmacol Toxicol. 2001;89:315–319. doi: 10.1034/j.1600-0773.2001.d01-167.x. [PubMed] [Cross Ref]
  • Chugh SN, Arora V, Sharma A, Chugh K. Free radical scavengers & lipid peroxidation in acute aluminium phosphide poisoning. Indian J Med Res. 1996;104:190–193. [PubMed]
  • Lam WW, Toia RF, Casida JE. Oxidatively initiated phosphorylation reactions of phosphine. J Agric Food Chem. 1991;39:2274–78. doi: 10.1021/jf00012a036. [Cross Ref]
  • Garry VF, Lyubimov AV. Phosphine. In: Krieger RI, editor. Handbook of Pesticide Toxicology. 2. Vol. 2. San Diego: Academic Press; 2001. pp. 1861–1866.
  • Potter WT, Garry VF, Kelly JT, Tarone R, Griffith J, Nelson RL. Radiometric assay of red cell and plasma cholinesterase in pesticide appliers from Minnesota. Toxicol Appl Pharmacol. 1993;119:150–155. doi: 10.1006/taap.1993.1054. [PubMed] [Cross Ref]
  • Potter WT, Rong S, Griffith J, White J, Garry VF. Phosphine-mediated Heinz body formation and hemoglobin oxidation in human erythrocytes. Toxicol Lett. 1991;57:37–45. doi: 10.1016/0378-4274(91)90117-O. [PubMed] [Cross Ref]
  • Amr MM, Abbas EZ, El-Samra M, El BM, Osman AM. Neuropsychiatric syndromes and occupational exposure to zinc phosphide in Egypt. Environ Res. 1997;73:200–206. doi: 10.1006/enrs.1997.3736. [PubMed] [Cross Ref]
  • Mendrala AL, Markham DA, Eisenbrandt DL. Rapid uptake, metabolism, and elimination of inhaled sulfuryl fluoride fumigant by rats. Toxicol Sci. 2005;86:239–247. doi: 10.1093/toxsci/kfi196. [PubMed] [Cross Ref]
  • EPA 40 CFR Part 180 [OPP-2003-0373; FRL-7342-1] Sulfuryl Fluoride; Pesticide Tolerance. Action: Final Rule. 69 FR 3240 (January 23, 2004)
  • Nuckolls JG, Smith DC, Walls WE, Oxley DW, Hackler RL, Tripathi RK, Armstron CW, Miller GB. Fatalities resulting from sulfuryl fluoride exposure after home fumigation – Virginia. JAMA. 1987;258:2041–44. doi: 10.1001/jama.258.15.2041. [PubMed] [Cross Ref]
  • Anger WK, Moody L, Burg J, Brightwell WS, Taylor BJ, Russo JM, Dickerson N, Setzer JV, Johnson BL, Hicks K. Neurobehavioral evaluation of soil and structural fumigators using methyl bromide and sulfuryl fluoride. Neurotoxicology. 1986;7:137–156. [PubMed]
  • Calvert GM, Mueller CA, Fajen JM, Chrislip DW, Russo J, Briggle T, Fleming LE, Suruda AJ, Steenland K. Health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers. Am J Public Health. 1998;88:1774–1780. [PubMed]
  • Hanley TR, Jr, Calhoun LL, Kociba RJ, Greene JA. The effects of inhalation exposure to sulfuryl fluoride on fetal development in rats and rabbits. Fundam Appl Toxicol. 1989;13:79–86. doi: 10.1016/0272-0590(89)90308-4. [PubMed] [Cross Ref]
  • Garry VF, Harkins ME, Erickson LL, Long-Simpson LK, Holland SE, Burroughs BL. Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. Environ Health Perspect. 2002;110:441–449. [PMC free article] [PubMed]
  • Piccirillo VJ. Methyl Bromide. In: Krieger RI, editor. Handbook of Pesticide Toxicology. 2. Vol. 2. San Diego: Academic Press; 2001. pp. 1837–47.
  • Nielsen E, Thorup I, Schnipper A, Hass U, Meyer O, Ladefoged O, Larsen JC, Østergaard G. Children and the unborn child: exposure and susceptibility to chemical substances – an evaluation. Denmark: The Institute of Food Safety and Toxicology, Danish Veterinary and Food Administration; 2001.
  • Roman GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci. 2007;262:15–26. doi: 10.1016/j.jns.2007.06.023. [PubMed] [Cross Ref]
  • Garry VF. Pesticides and children. Toxicol Appl Pharmacol. 2004;198:152–163. doi: 10.1016/j.taap.2003.11.027. [PubMed] [Cross Ref]
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