Evaluation of human relevance and mode of action for tunica vaginalis mesotheliomas resulting from oral exposure to acrylamide.

The human relevance and mode of action of acrylamide-related tunica vaginalis mesotheliomas (TVMs), a tumor of the scrotum, was evaluated based on the available data on acrylamide and general biology considerations. TVMs are found almost exclusively in F344 rats, suggesting an association with the hormonal milieu unique to F344s, and suggesting an association with Leydig cell tumors (LCTs), which occur in F344 rats at a very high incidence. These hypotheses are biologically plausible, but direct data on acrylamide were lacking for several key events; some of the gaps could be addressed based on other biology information. The data were not sufficient to identify a single definitive MOA. Multiple MOAs may apply, and some contribution from mutagenicity is plausible, along with a likely influence from LCTs or from the same hormonal changes that result in higher LCT incidence in F344 rats. Other MOAs, such as oxidative stress, may also apply. The data reviewed are not sufficient to distinguish between a causal relationship between LCTs and TVMs, and the hypothesis that these tumor types reflect a response to some shared influence (e.g., hormonal milieu of the F344 rat). Some of the plausible MOAs are not relevant to humans, while others are. In light of the very low incidence of TVMs in humans and the MOA data reviewed, the most appropriate upper bound estimate of the risk of acrylamide-related TVMs in humans is below de minimis levels.

Lessons learned, challenges, and opportunities: the U.S. Endocrine Disruptor Screening Program.

In 1996, the U.S. Congress passed the Food Quality Protection Act and amended the Safe Drinking Water Act (SDWA) requiring the U.S. Environmental Protection Agency (EPA) to implement a screening program to investigate the potential of pesticide chemicals and drinking water contaminants to adversely affect endocrine pathways. Consequently, the EPA launched the Endocrine Disruptor Screening Program (EDSP) to develop and validate estrogen, androgen, and thyroid (EAT) pathway screening assays and to produce standardized and harmonized test guidelines for regulatory application. In 2009, the EPA issued the first set of test orders for EDSP screening and a total of 50 pesticide actives and 2 inert ingredients have been evaluated using the battery of EDSP Tier 1 screening assays (i.e., five in vitro assays and six in vivo assays). To provide a framework for retrospective analysis of the data generated and to collect the insight of multiple stakeholders involved in the testing, more than 240 scientists from government, industry, academia, and non-profit organizations recently participated in a workshop titled "Lessons Learned, Challenges, and Opportunities: The U.S. Endocrine Disruptor Screening Program." The workshop focused on the science and experience to date and was organized into three focal sessions: (a) Performance of the EDSP Tier 1 Screening Assays for Estrogen, Androgen, and Thyroid Pathways; (b) Practical Applications of Tier 1 Data; and (c) Indications and Opportunities for Future Endocrine Testing. A number of key learnings and recommendations related to future EDSP evaluations emanated from the collective sessions.