Chapter

Molecular, Clinical and Environmental Toxicology

Volume 101 of the series Experientia Supplementum pp 361-379

Date:

Interspecies Uncertainty in Molecular Responses and Toxicity of Mixtures

  • Moiz M. MumtazAffiliated withDivision of Toxicology and Human Health Sciences, Agency of Toxic Substances and Disease Registry (ATSDR)U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) Email author 
  • , Hana R. PohlAffiliated withDivision of Toxicology and Human Health Sciences, Agency of Toxic Substances and Disease Registry (ATSDR)U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC)

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Abstract

Most of the experimental toxicity testing data for chemicals are generated through the use of laboratory animals, namely, rodents such as rats and mice or other species. Interspecies extrapolation is needed to nullify the differences between species so as to use such data for human health/risk assessment. Thus, understanding of interspecies differences is important in extrapolating the laboratory results to humans and conducting human risk assessments based on current credible scientific knowledge. Major causes of interspecies differences in anatomy and physiology, toxicokinetics, injury repair, molecular receptors, and signal transduction pathways responsible for variations in responses to toxic chemicals are outlined. In the risk assessment process, uncertainty associated with data gaps in our knowledge is reflected by application of uncertainty factors for interspecies differences. Refinement of the risk assessment methods is the ultimate goal as we strive to realistically evaluate the impact of toxic chemicals on human populations. Using specific examples from current risk assessment practice, this chapter illustrates the integration of interspecies differences in evaluation of individual chemicals and chemical mixtures.

Keywords

Chemical interactions Complex mixtures Cytochrome P450-dependent monooxygenases Interspecies variation Metabolic variation Molecular receptor variation 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Minimal risk level Human equivalent concentration Signal transduction variation Risk assessment Threshold limit values Tissue repair variation Toxic equivalent Weight of evidence