Application of pharmacokinetic modelling for 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure assessment

^£Presented at the 16th International Workshop on Quantitative Structure–Activity Relationships in Environmental and Health Sciences (QSAR2014), 16–20 June 2014, Milan, Italy.

Abstract

Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (dioxin-like PCBs) are identified as a family or group of organic compounds known as ‘dioxins’ or dioxin-like chemicals (DLCs). The most toxic member of this group is 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD). Historically, DLCs have caused a variety of negative human health effects, but a disfiguring skin condition known as chloracne is the only health effect reported consistently. As part of translational research to make computerized models accessible to health risk assessors, the Concentration- and Age-Dependent Model (CADM) for TCDD was recoded in the Berkeley Madonna simulation language. The US Agency for Toxic Substances and Disease Registry’s computational toxicology laboratory used the recoded model to predict TCDD tissue concentrations at different exposure levels. The model simulations successfully reproduced the National Health and Nutrition Examination Survey (NHANES) 2001–2002 TCDD data in age groups from 6 to 60 years and older, as well as in other human datasets. The model also enabled the estimation of lipid-normalized serum TCDD concentrations in breastfed infants. The model performed best for low background exposures over time compared with a high acute poisoning case that could due to the large dose and associated liver toxicity. Hence, this model may be useful for interpreting human biomonitoring data as a part of an overall DLC risk assessment.

Keywords:

• PBPK
• 2,3,7,8-tetrachlorodibenzo-p-dioxin
• TCDD
• dioxins
• NHANES

Acknowledgements

The authors are grateful to Dr Ted W. Simon and Dr Clem Welsh for their valuable support, discussions and advice during the project. We also appreciate Mr Jesse Thompson and Miss Irish Angie Frey for their graphic and editorial technical support respectively.

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry. Mention of trade names is not an endorsement of any commercial product.

Notes

^£ Presented at the 16th International Workshop on Quantitative Structure–Activity Relationships in Environmental and Health Sciences (QSAR2014), 16–20 June 2014, Milan, Italy.