1. Cumulative Risk Assessment: A Critical Step Forward in Human Health Protection Deborah A. Cory-Slechta Department of Environmental Medicine University of Rochester School of Medicine Rochester, NY

2. Purpose of Risk Assessment  Determine the extent to which chemical exposures may be associated with human health effects, i.e., relations to human diseases and disorders

3. Cumulative Risk Assessment  Current practice Risk assessment is based on effects of single chemical exposures  A few exceptions: Chemicals with structural similarity that act on a single molecular target site  dioxins, PCBs  Organophosphate pesticides Superfund site assessments  Notably, these mixtures constitute only a very tiny fraction of the chemical mixtures problem

4. Cumulative Risk Assessment  But humans are actually exposed to multiple chemicals at the same time, in addition to non-chemical stressors: Chemicals that are not related in structure nor do they have actions at a single molecular target site

5. But They Can Nevertheless Be Associated with the Same Adverse Health Outcomes  Chemicals associated with reduced IQ in children: e.g., Lead, mercury, PCBs  Chemicals associated with hypertension: Lead, methylmercury, arsenic, dioxins, organic solvents  Chemicals associated with Parkinson’s disease in epidemiological studies e.g., Paraquat, maneb, rotenone, lead

6. Unrelated Chemicals Can be Associated with the Same Adverse Health Outcomes  Chemicals with very different structures and different molecular target sites and would therefore escape current cumulative risk assessment practices  As research is now beginning to confirm, such chemicals may have the potential to act additively or even synergistically, even when tested at below threshold doses.

7. Why Has Cumulative Risk Stalled?  The most often stated EPA reasons: “There are 80,000 chemicals out there. Where would we start?”

8. NAS Committee on Phthalates and Cumulative Risk Assessment  As part of its charge, this committee devoted considerable time to: Considering the strengths and weaknesses of cumulative risk assessment approaches The applicability of its recommendations for conducting cumulative risk assessment for chemicals  Arrived at a recommendation and a road map forward

9. Phthalates Cause Male Reproductive Anomalies by Decreasing Levels of the Hormone Androgen  There are many different pathways, however, that can lower androgen levels  The body doesn’t care which pathways are activated, i.e., how it happens.  The body simply recognizes that it doesn’t have enough androgen

10. Consequently, to Protect Public Health and Estimate True Risks, Other Anti-Androgens Have to be Included  Cumulative Risk for Male Reproductive Hazards: Phthalates Vinclozolin Linuron Azole fungicides Dioxins

11. Indeed, New Studies Demonstrate Additive Toxicity Rider et al., 2009 Cumulative Effects of In Utero Administration Of Mixtures of “Antiandrogens” on Male Rat Reproductive Development We also conducted a mixture study combining seven“antiandrogens” together. These chemicals elicit antiandrogenic effects at two different sites in the androgen signaling pathway (i.e., AR antagonist or inhibition of androgen synthesis). In this study, the complex mixture behaved in a dose-additive manner. Our results indicate that compounds that act by disparate mechanisms of toxicity display cumulative dose-additive effects when present in combination.

12. True Estimate of Public Health Risks  Then, currently:  Where we need to go: We’re picking the low-hanging fruit, i.e., single chemicals with the largest effects on human health Cumulative Risk If chemicals have effects at lower levels when they occur with other chemical exposures, then we are potentially significantly underestimating their health risks

13. This Strategy Should Be Generally Applied to Cumulative Risk Assessment  In the view of the Committee, such cumulative risks strategies should not be specific to phthalates: “…the Committee concludes that it is plausible and warranted to extend cumulative risk assessment to include chemicals associated with common adverse outcomes as exemplified in this report by inclusion of other antiandrogenic chemicals with phthalates.”

14. Impaired Cognitive Development Pb MeHg SGAPCBs FAS Maternal Infection Concurrent Risks A Cumulative Risk Road Map  “To cite another example, EPA could evaluate combined exposures to lead, methylmercury and polychlorinated biphenyls because all contribute to the cumulative risk of cognitive deficits associated with IQ reductions in children, although the deficits are produced by different mechanisms of action.”

15. A Road Map for Cumulative Risk  This strategy allows us to define important mixtures to study by choosing those we already know to be associated with a specific disease or disorder Once the disease of interest is identified, incorporate those chemicals already known to be associated with that disease We already know what many chemicals do by themselves and we can exploit that information HYPERTENSION Lead Organic Solvents Methylmercury Arsenic

16. A Road Map for Cumulative Risk  A strategy far more consistent with human physiology and what we know about how human diseases occur  Consistent with EPA’s mission to protect public health by focusing on human diseases and disorders  A strategy that the public clearly ‘gets’ Most of the intractable diseases and disorders are considered to reflect the interactions of multiple factors and their interactions

17. Economics and Cost/Benefit  Any increase in regulatory costs could be offset: Focus initially on diseases/disorders of greatest economic and societal impact to determine the role of chemical exposures Determine the economic benefit of controlling/mitigating those exposures

18. Adding Non-Chemical Stressors to Cumulative Risk: A Longer Term Goal  The ‘gold standard’ of ultimately understanding human diseases and disorders includes, e.g.: Genetic polymorphisms Stress Inter-current disease state Period of development/stage of the life cycle  These could be added later as the strategies for cumulative risk based on multiple chemical exposures become better established To some extent these are now accommodated by adding uncertainty factors to the risk assessment

19. Clearly Represents a Paradigm Shift for EPA  But it has in place many of the intellectual resources to move this forward.  What is required at the end of the day, is the regulatory requirement