A look at state-level risk assessment in the United States: making decisions in the absence of federal risk values.

State environmental agencies in the United States are charged with making risk management decisions that protect public health and the environment while managing limited technical, financial, and human resources. Meanwhile, the federal risk assessment community that provides risk assessment guidance to state agencies is challenged by the rapid growth of the global chemical inventory. When chemical toxicity profiles are unavailable on the U.S. Environmental Protection Agency's Integrated Risk Information System or other federal resources, each state agency must act independently to identify and select appropriate chemical risk values for application in human health risk assessment. This practice can lead to broad interstate variation in the toxicity values selected for any one chemical. Within this context, this article describes the decision-making process and resources used by the federal government and individual U.S. states. The risk management of trichloroethylene (TCE) in the United States is presented as a case study to demonstrate the need for a collaborative approach among U.S. states toward identification and selection of chemical risk values while awaiting federal risk values to be set. The regulatory experience with TCE is contrasted with collaborative risk science models, such as the European Union's efforts in risk assessment harmonization. Finally, we introduce State Environmental Agency Risk Collaboration for Harmonization, a free online interactive tool designed to help to create a collaborative network among state agencies to provide a vehicle for efficiently sharing information and resources, and for the advancement of harmonization in risk values used among U.S. states when federal guidance is unavailable.

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.

Resources for global risk assessment: the International Toxicity Estimates for Risk (ITER) and Risk Information Exchange (RiskIE) databases.

The rate of chemical synthesis and use has outpaced the development of risk values and the resolution of risk assessment methodology questions. In addition, available risk values derived by different organizations may vary due to scientific judgments, mission of the organization, or use of more recently published data. Further, each organization derives values for a unique chemical list so it can be challenging to locate data on a given chemical. Two Internet resources are available to address these issues. First, the International Toxicity Estimates for Risk (ITER) database (www.tera.org/iter) provides chronic human health risk assessment data from a variety of organizations worldwide in a side-by-side format, explains differences in risk values derived by different organizations, and links directly to each organization's website for more detailed information. It is also the only database that includes risk information from independent parties whose risk values have undergone independent peer review. Second, the Risk Information Exchange (RiskIE) is a database of in progress chemical risk assessment work, and includes non-chemical information related to human health risk assessment, such as training modules, white papers and risk documents. RiskIE is available at http://www.allianceforrisk.org/RiskIE.htm, and will join ITER on National Library of Medicine's TOXNET (http://toxnet.nlm.nih.gov/). Together, ITER and RiskIE provide risk assessors essential tools for easily identifying and comparing available risk data, for sharing in progress assessments, and for enhancing interaction among risk assessment groups to decrease duplication of effort and to harmonize risk assessment procedures across organizations.

Evidence-based dose-response assessment for thyroid tumorigenesis from acrylamide.

Acrylamide is commonly found in various foods. Cancer studies in rats have reported increases in tumors of the thyroid, mammary tissues, tunica vaginalis of the testis, and sometimes tumors at other sites. We review relevant studies on acrylamide's DNA toxicity, tumor formation and the manner of its tumor formation. We find, as do others, that glycidamide (a metabolite of acrylamide) causes point mutations, but acrylamide does not. We also find that thyroid tumors are most consistently sensitive in rats, being evoked in each of four long-term experiments. We evaluate the common manners of this tumor formation in the thyroid, including both mutagenicity and thyroid growth-stimulation. Consistent with the overall weight of the evidence, we conclude that both of these manners or modes of action may be occurring. We conservatively assume that the mutagenic mode of action determines the low-dose-response and we conclude that growth stimulation likely dominates the response at higher doses. Following US EPA guidelines, we determined that the probit model best reflects the overall data set; this model is also preferred because it better reflects the underlying "decoupled" biology of contributions from potentially two modes of action. We use the probit model to identify a health-protective, linear cancer slope factor (SF) of 0.030 (mg/kg-day)(-1) for the low area of the dose-response curve associated with possible mutagenicity. We also identify a Reference Dose (RfD) in the range of 0.05-0.02 mg/kg-day for the high area of the dose-response curve associated with the growth stimulation. This latter value can be used to determine the upper range of risk. This dose-response assessment is briefly summarized in light of other related work.

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.