Using quantitative modeling tools to assess pharmacokinetic bias in epidemiological studies showing associations between biomarkers and health outcomes at low exposures

• Published in: Environmental research Vol. 197; p. 111183
• Main Authors: Andersen, Melvin E., Mallick, Pankajini, Clewell, Harvey J., Yoon, Miyoung, Olsen, Geary W., Longnecker, Matthew P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.06.2021
• ISSN: 0013-9351; 1096-0953
• DOI: 10.1016/j.envres.2021.111183

Biomarkers of exposure can be measured at lower and lower levels due to advances in analytical chemistry. Using these sensitive methods, some epidemiology studies report associations between biomarkers and health outcomes at biomarker levels much below those associated with effects in animal studies. While some of these low exposure associations may arise from increased sensitivity of humans compared with animals or from species-specific responses, toxicology studies with drugs, commodity chemicals and consumer products have not generally indicated significantly greater sensitivity of humans compared with test animals for most health outcomes. In some cases, these associations may be indicative of pharmacokinetic (PK) bias, i.e., a situation where a confounding factor or the health outcome itself alters pharmacokinetic processes affecting biomarker levels. Quantitative assessment of PK bias combines PK modeling and statistical methods describing outcomes across large numbers of individuals in simulated populations. Here, we first provide background on the types of PK models that can be used for assessing biomarker levels in human population and then outline a process for considering PK bias in studies intended to assess associations between biomarkers and health outcomes at low levels of exposure. After providing this background, we work through published examples where these PK methods have been applied with several chemicals/chemical classes - polychlorinated biphenyls (PCBs), perfluoroalkyl substances (PFAS), polybrominated biphenyl ethers (PBDE) and phthalates - to assess the possibility of PK bias. Studies of the health effects of low levels of exposure will be improved by developing some confidence that PK bias did not play significant roles in the observed associations. •Pharmacokinetic (PK) bias may cause low exposure associations with outcomes.•Physiological variation or pathophysiology can alter biomarker pharmacokinetics.•Both simple and physiologically based PK models are well-suited to assessing PK bias.•PK bias analyses use both PK modeling and population simulations.•PK bias analysis is a useful method of bias assessment in selected settings.