Role of epidemiology in risk assessment: a case study of five ortho-phthalates

Background The association between environmental chemical exposures and chronic diseases is of increasing concern. Chemical risk assessment relies heavily on pre-market toxicity testing to identify safe levels of exposure, often known as reference doses (RfD), expected to be protective of human health. Although some RfDs have been reassessed in light of new hazard information, it is not a common practice. Continuous surveillance of animal and human data, both in terms of exposures and associated health outcomes, could provide valuable information to risk assessors and regulators. Using ortho-phthalates as case study, we asked whether RfDs deduced from male reproductive toxicity studies and set by traditional regulatory toxicology approaches sufficiently protect the population for other health outcomes. Methods We searched for epidemiological studies on benzyl butyl phthalate (BBP), diisobutyl phthalate (DIBP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), and bis(2-ethylhexyl) phthalate (DEHP). Data were extracted from studies where any of the five chemicals or their metabolites were measured and showed a statistically significant association with a health outcome; 38 studies met the criteria. We estimated intake for each phthalate from urinary metabolite concentration and compared estimated intake ranges associated with health endpoints to each phthalate’s RfD. Result For DBP, DIBP, and BBP, the estimated intake ranges significantly associated with health endpoints were all below their individual RfDs. For DEHP, the intake range included associations at levels both below and above its RfD. For DCHP, no relevant studies could be identified. The significantly affected endpoints revealed by our analysis include metabolic, neurodevelopmental and behavioral disorders, obesity, and changes in hormone levels. Most of these conditions are not routinely evaluated in animal testing employed in regulatory toxicology. Conclusion We conclude that for DBP, DIBP, BBP, and DEHP current RfDs estimated based on male reproductive toxicity may not be sufficiently protective of other health effects. Thus, a new approach is needed where post-market exposures, epidemiological and clinical data are systematically reviewed to ensure adequate health protection.

Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation

The adverse outcome pathway (AOP) framework provides a practical means for organizing scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. It has reached wide acceptance as a tool to aid chemical safety assessment and regulatory toxicology by supporting a systematic way of predicting adverse health outcomes based on accumulated mechanistic knowledge. A major challenge for broader application of the AOP concept in regulatory toxicology, however, has been developing robust AOPs to a level where they are peer reviewed and accepted. This is because the amount of work required to substantiate the modular units of a complete AOP is considerable, to the point where it can take years from start to finish. To help alleviate this bottleneck, we propose a more pragmatic approach to AOP development whereby the focus becomes on smaller blocks. First, we argue that the key event relationship (KER) should be formally recognized as the core building block of knowledge assembly within the AOP knowledge base (AOP-KB), albeit framing them within full AOPs to ensure regulatory utility. Second, we argue that KERs should be developed using systematic review approaches, but only in cases where the underlying concept does not build on what is considered canonical knowledge. In cases where knowledge is considered canonical, rigorous systematic review approaches should not be required. It is our hope that these approaches will contribute to increasing the pace at which the AOP-KB is populated with AOPs with utility for chemical safety assessors and regulators.