In the relatively short time (7–8 years) that sensitive biomarkers for assaying human phthalate exposure in humans have been available, a rapidly growing literature has demonstrated that human exposure is ubiquitous, and evidence for significant impacts on human health is mounting. As seen in this review, most studies in both the toxicological and human literature have reported associations with prenatal and postnatal phthalate exposure in males. This may be a consequence of the anti-androgenic mode of action of the most toxic of these chemicals. In addition (as was learned from the delay in detecting effects of diethylstilbestrol in females), alteration in the female genital tract are hidden and may be missed until puberty or adulthood.
Epidemiological studies may be the “gold standard” for assessing risks to human health, but these are expensive (costing upwards of one-million US dollars per study) and slow (typically a minimum of five years from conception of a human health study to results). Moreover, epidemiology is limited in its ability to draw causal inferences. Therefore, it must be informed by, and closely linked to, animal studies in which mechanism and causality can be demonstrated. While several links between rodent and human studies have been made in this area, as discussed above, these are limited by several discrepancies between human and animal testing.
Animal testing of phthalates has been, for the most part, conducted at doses far higher than those present in the ambient human environment. If dose responses are nonlinear, as has been demonstrated for other environmental chemicals, this testing strategy will not protect human health (Vom Saal al., 2005
). In addition, until recently phthalates were tested singly, while humans are exposed to multiple phthalates simultaneously. Recent rodent data suggest that exposure to multiple phthalates at low doses conveys risk in a dose additive manner (Gray et al., 2006
; Howdeshell et al., 2008
). This suggests that the risk from a mixture of phthalates (or phthalates and other anti-androgens), whether acting by similar mechanisms or not, cannot be accurately assessed studying one chemical at a time.
The same may be true of risks from multiple exposure routes. For example, most toxicological testing of phthalate is via oral exposure. However, humans are exposed to phthalates by a multiplicity of routes. For DEP, and its metabolite MEP, human exposure is predominantly dermal. For example, Janjua et al. (Janjua et al., 2007
) recently demonstrated systemic dermal uptake of MEP and MBP in male volunteers by measuring these in serum and urine following whole body topical application of cream containing these compounds. Whether differences in exposure route can account for differences in the toxicology of this phthalate in humans and rodents in not clear.
Because of these important differences in route, dose level and multiplicity of agents, it is often unclear how to interpret findings across species. For these reasons, if chemical risk assessment is to be relevant to human exposure, future assessments should incorporate more environmentally relevant scenarios, including mixtures.