Citation:

Conley, J., C. Lambright, N. Evans, M. Cardon, J. Furr, V. Wilson, AND E. Gray. Mixed “antiandrogenic” chemicals at low individual doses produce reproductive tract malformations in the male rat. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 164(1):166-178, (2018).

Impact/Purpose:

The USEPA is required by federal law (Food Quality Protection Act, Safe Drinking Water Act) to assess the cumulative risk of exposure to chemicals that are toxicologically similar. Thus far Agency efforts have focused on grouping chemicals for cumulative risk assessment based on chemical similarity (e.g., organophosphate pesticides). Research from our group, detailed in the present manuscript, demonstrates the need to more broadly group chemicals that target a similar biological signaling pathway - in this case, fetal male reproductive development coordinated via the androgen receptor. Further, we demonstrate the use of Adverse Outcome Pathway networks (AOPn) for identifying chemicals with disparate MIEs that target a common pathway and may be suitable for cumulative risk assessment.

Description:

Biomonitoring efforts have clearly shown that all humans are exposed to chemical mixtures. Of concern is whether or not exposure to mixtures during pregnancy contributes to congenital abnormalities in children even when each chemical is at an individual dose that does not affect the fetus. Here, we hypothesized that in utero exposure to a mixture of chemicals covering multiple “anti-androgenic” mechanisms of action at doses that have no adverse effect in utero would result in permanent reproductive tract alterations in the male rat after birth. Pregnant dams were exposed to a range of dilutions (100, 50, 25, 12.5, 6.25%, or control) of a mixture containing pesticides, phthalates and drugs (p,p’-DDE, linuron, prochloraz, procymidone, pyrifluquinazon, vinclozolin, finasteride, flutamide, simvastatin, and 9 phthalates (dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl)). The top dose contained each chemical at 20% of its lowest observed adverse effect level (LOAEL) for the most sensitive male reproductive alteration following in utero exposure. We found that male rat offspring displayed a variety of neonatal, pubertal, and permanent adult effects across all dose levels. Even at the lowest dose (each chemical ~80-fold below LOAEL) there were permanent reductions in several reproductive tract tissue weights. In the top dose group, 100% of male offspring displayed permanent severe birth defects including genital malformations. Despite multiple mechanisms of action, exposure during pregnancy to a mixture of 18 chemicals at doses 80-fold below the individual chemical LOAELS resulted in permanent, congenital reproductive alterations

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