Developmental Toxicity Risk Assessment

The EPA Guidelines for Developmental Toxicity Risk Assessment (1991) discuss how various types of developmental toxicity data should be considered in hazard characterization and dose-response analysis, and their integration with exposure information in risk characterization. In those guidelines, developmental toxicity is defined as:

the study of adverse effects on the developing organism that may result from exposure prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the lifespan of the organism. The major manifestations of developmental toxicity include: (1) death of the developing organism, (2) structural abnormality, (3) altered growth, and (4) functional deficiency.

Although not discussed in any detail in those guidelines, developmental immu-notoxicity is considered part of developmental toxicity, as is developmental neurotoxicity or any other type of functional alteration resulting from an exposure during the developmental period (conception to sexual maturity). In the case of developmental neurotoxicity, further guidance is given in the Guidelines for Neurotoxicity Risk Assessment (USEPA 1998a), and the same approach might be considered for development of guidelines for immunotoxicity risk assessment that would include the assessment of potential effects on the immune system at multiple life stages.

Dose-response assessment for health effects that are not assumed to have a linear low-dose response relationship (i.e., most noncancer health effects and carcinogens that act via indirect mechanisms) is conducted by applying various uncertainty factors (UFs) to the no-observed-adverse-effect level (NOAEL) or a benchmark dose lower confidence limit (BMDL) if dose-response modeling can be done. A default 10-fold factor is used for the UFs, and various factors are applied to account for animal to human extrapolation (UFA), within human variability (UFH), the lack of a NOAEL and use of the lowest-observed-adverse-effect level, LOAEL (UFL), use of a subchronic study to set a chronic reference value when no chronic study is available (UFS), and a database factor (UFD) to account for missing data that are considered essential in characterizing risk. If the exposure is by inhalation, the animal to human extrapolation UF is divided into pharmacokinetic and pharmacodynamic components. EPA has developed methodology for deriving appropriate conversions for inhalation exposures to account for the pharmacokinetic component of the extrapolation (USEPA 1994), so that the UFA applied as a default in the case of inhalation exposures is 1012. An additional 10-fold FQPA factor is applied for pesticides, but is acknowledged to overlap with several of the traditional UFs; thus, the FQPA factor may be reduced or removed, depending on the quality of the data on children's health and exposure, e.g., residual concerns about controlling exposures to children may result in retention of the FQPA factor (USEPA 2002a).

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