Reproductive and developmental toxicity

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

No developmental and reproductive toxicity data on humans concerning aniline were identified in the available literature. 

No studies addressing developmental or reproductive effects following acute inhalation exposure to aniline were located. However, because effects on development and reproduction arise after systemic uptake, oral administration of aniline can be considered for evaluating potential developmental and reproductive toxicity. Aniline (administered as aniline hydrochloride) readily crosses the placental barrier in rodents (Price et al. 1985). 

Homung, M.W., L. Miller, B. Goodman, M.J. Melancon, and R.E. Peterson. 1998. Lack of developmental and reproductive toxicity of 2,3,3, 4,4 -pentachlorobiphenyl (PCB 105) in ring-necked pheasants. Arch. Environ. Contam. Toxicol. 35 646-653. 

Developmental and reproductive toxicity studies regarding animal exposure to phosgene were not available. 

Data adequacy The key study was well designed, conducted, and documented used 20 human subjects and utilized a range of concentrations and exposure durations. Occupational exposures support the 8-h AEGL value. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity. ... 

Developmental and Reproductive Toxicity. This was an area in which there was considerable international disagreement and the area in which ICH has promulgated the most technically detailed guidelines (S5A and S5B). Some of the major changes include ... 

This chapter briefly describes the current standard study designs and then focuses on current issues in developmental and reproductive toxicity testing. 

Statistical analysis is a very useful tool for evaluating the effects of treatment on many developmental and reproductive toxicity parameters. For some parameters, such as maternal body weight changes, fetal weight, and horizontal activity in an open field, the comparison to the concurrent control is the primary consideration and, assuming adequate group size, the investigator relies heavily on the results of appropriate statistical analyses to interpret differences from control. 

Statistical methods exist to appropriately analyze most developmental and reproductive toxicity parameters. Exceptions to this are the r/m litter parameters in which, for each litter, there is a number affected divided by the number in the litter. These parameters include preimplantation loss (r = corpora lutea - implants, m = corpora lutea), resorption rate (r = resorptions, m = implants), and the family of alteration rates (r = affected fetuses, m = fetuses). There are two factors complicating the statistical analysis of these data that have heretofore been inadequately handled (Clark et al., 1989). One is that almost all of these parameters have a strong dependence on m. For example, both preimplantation loss (Figure 8.4)... 

Antonello, J.M., Clark, R.L. and Heyse, J.F. (1993). Application of Tahey Trend Test procedures to assess developmental and reproductive toxicity. I. Measurement data. Fundam. Appl. Toxicol. 21 52-58. 

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