The finding in April 2002 of elevated levels of acrylamide in a variety of foodstuffs were unexpected, and led to a call by public health scientists for additional research on acrylamide (WHO, 2002
). Reports from laboratory studies a few months later have provided insight into the biochemical mechanism of acrylamide formation. Acrylamide can be generated during the heating of specific foodstuffs as a result of a Maillard reaction between amino acids and sugars (Mottram et al, 2002
; Stadler et al, 2002
). In particular, acrylamide formation occurs when the amino acid asparagine, in the presence of sugars, is heated above 100°C. Potatoes and cereals, which had the highest measured levels of acrylamide in the Swedish NFA survey, are rich in asparagine (Belitz and Grosch, 1999
This population-based case–control study found no association between dietary exposure to acrylamide in amounts typically ingested by Swedish adults and risk of cancers of the large bowel, bladder, or kidney. For foods with the highest acrylamide levels, namely, potato crisps, French fries, and crisp bread, there was no positive association with cancer risk. Indeed, the risk of cancer of the large bowel decreased with increasing dose of dietary acrylamide. We did observe a slightly higher risk of bladder cancer for those consuming baked or fried potatoes daily compared to never, although the CI includes the null value. Although this positive finding is in line with a previous study (Steineck et al, 1990
), our findings overall suggest that components of potatoes other than acrylamide are responsible for this association.
The classification of acrylamide by IARC as a probable human carcinogen (IARC, 1994
) was based mainly on in vitro
and animal models. Acrylamide induces genetic mutations and chromosomal abnormalities in vitro
, and cellular transformation in vivo
). Long-term studies in rats and mice supported a dose–exposure relation between acrylamide and risk of cancer of the lung, mammary gland, thyroid, oral cavity, and intestinal and reproductive tract (Bull et al, 1984
; Johnson et al, 1986
). Moreover, animals administered acrylamide orally (Paulsson et al, 2002
) or fed a diet high in fried foods (Tareke et al, 2000
) had higher levels of haemoglobin DNA adducts compared to unexposed animals.
The human data were less clear and limited to occupational settings. In a small cohort of 371 workers exposed to acrylamide through organic dyes, cancer mortality was higher than expected, mainly because of deaths from cancer of the digestive tract and respiratory system (Sobel et al, 1986
). More recently, Marsh et al, (1999)
in a cohort of 8500 workers with potential occupational exposure found little evidence for an excess risk of cancer mortality overall. While an excess of thyroid cancer and a dose–exposure relation with pancreatic cancer were suggested, the wide CIs precluded definitive assessments. The study had greater power to detect an effect of lung cancer, which showed minimal excess risk between both workers exposed and unexposed to acrylamide compared to the general population. Among 200 construction workers exposed to high levels of acrylamide for 20 months, 80% had haemoglobin adduct levels above the normal background range (Hagmar et al, 2001
One interpretation of our null finding is that no association between dietary acrylamide and cancer risk exists, implying that species differences negate extrapolating from experimental animals to humans, as shown for other carcinogens (IARC, 1987
). In addition, human intake of dietary acrylamide is several folds lower than doses tested in animal experiments. Acrylamide intake within the range of human exposure may thus be effectively detoxified. Although a comprehensive coverage of dietary acrylamide was not possible, certain aspects of our study would support the validity of its negative findings. It was large and population-based with reasonably high response rates, thus reducing the possibility of selection bias while the data on demographic, lifestyle, and dietary, covariates would have reduced the opportunity for confounding in the analysis.
Could certain limitations and possible biases have attenuated a true positive association? First, the acrylamide content of a number of food items has not yet been characterised, so our values of daily intake of dietary acrylamide may be underestimated. Measurement errors of acrylamide intake in cases and controls would entail such attenuation (Rothman and Greenland, 1998
). There was also variability in acrylamide dose across brands of a given food. It is relevant that it is ranking of individuals with respect to exposure, rather than absolute intake, that determines the calculated relative risk in case–control studies. In fact, when comparing an abbreviated vs
extensive food frequency questionnaire, increasing the number of food items improves the ranking, and thereby the relative risk, only to a small degree (Voskuil et al, 1999
). In our own data, we found the relative risk estimates comparing quartiles of total acrylamide dose to be insensitive to the concentration of acrylamide used to rank individual food items. Although we possibly capture only partial intake of acrylamide, it is likely that we have a ranking that is valid for drawing conclusions.
Second, a true association may be concealed if the level of exposure in the studied population is low and/or if the range of variation is limited. Of the food items found to contain the highest levels of acrylamide, only biscuits and pan-fried potatoes were commonly consumed by this population. Risk assessment models for humans suggest that lifetime risk for cancer is 0.7–4.5 per 1000 based on consumption of 1μ
g acrylamide per kg body weight per day (US EPA, 1985
; WHO, 1985
). In our study, less than 2% of the population was estimated to intake acrylamide through diet at these levels. Acrylamide intake through dietary sources may thus be effectively detoxified within the range of human exposure. This hypothesis is suggested for heterocyclic amines, which cause cancer when given to rodents, but does not appear to in humans, where doses are typically millionth of those given in studies of animal carcinogenicity (Augustsson et al, 1999
Third, residual confounding is a possible explanation for some of our findings, such as the inverse association between total acrylamide dose and large bowel cancer. The food items under study contain a multitude of nutrients. Although we have controlled analytically for total energy, saturated fat, meat, and fruits and vegetables, it may be difficult to disentangle the protective effect of specific nutrients from that of acrylamide. Lastly, although no excess risk was observed for the three major cancers studied, we cannot rule out a possible excess risk of other cancer sites. However, large bowel, bladder, and kidney would be likely target sites, because acrylamide and its metabolite glycidamide are detoxified by glutathione conjugation, are water soluble, and are absorbed quickly in the digestive tract and excreted via the urine (IARC, 1994
This first study of dietary acrylamide in relation to three major human cancers is reassuring. Needless to say, additional epidemiological evidence is required, notably for other cancer sites as well as for neurological and other disorders. While the null hypothesis of no effect can never be scientifically proven, it would be useful to determine cooking methods that avoid acrylamide formation during food preparation. Since measuring error in acrylamide intake would entail underestimation of any true association with cancer risk, validation studies of acrylamide dose using existing food questionnaires should be a high priority.