Reproductive and developmental toxicity test

Buschmann J (2006) Critical aspects in reproductive and developmental toxicity testing of environmental chemicals. Reprod Toxicol 22 157-163... 

Historical control data can also be obtained from other laboratories such as CROs, some of which have a long history of reproductive and developmental toxicity testing and have large multispecies historical control databases that can span decades, and are therefore very useful for observing long term trends. This type of data can be especially informative when looking for occurrences of rare malformations in controls. Charles River Laboratories (www.criver.com) is one CRO that has made its historical data for reproductive and developmental toxicity publicly available. Historical control data for the CD rat and the New Zealand White rabbit is also available in the literature (8, 9, 13-15). Other laboratories may provide data upon request. 

To reduce the number of reproductive and developmental disorders caused by exposure to chemical and physical agents, reproductive and developmental toxicity testing generally is conducted in laboratory animals because at present no other approach is considered predictive of reproductive and developmental effects and, also, data in humans... 

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

Lochry, E.A. (1987). Concurrent use of behavioral/functional testing in existing reproductive and developmental toxicity screens Practical consideration. J. Am. Coll. Toxicol. 6 433-439. 

Munro et al. (1996) explored the relationship between chemical structure and toxicities through the compilation of a large reference database consisting of 613 chemical substances tested for a variety of noncarcinogenic toxicological endpoints in rodents and rabbits in oral toxicity tests, including subchronic, chronic, reproductive, and developmental toxicity. For many of the substances, more... 

Reproductive and developmental toxicity studies in laboratory animals are conducted under regulatory testing guidelines (e.g., (1-3) as part of the process of evaluating the risk of pharmaceuticals and... 

Screening stady for reproductive and developmental toxicity (e.g., OECD Test Guideline No. 421 or 422)... 

The reproductive and developmental toxicity of diethanolamine tested has been reviewed (Knaak et al., 1997). 

The reproductive and developmental toxicity of triethanolamine tested without the complication of many other accompanying substances has been reviewed (Knaak etal., 1997). This review is used as the reference source to the following studies because they have not been reported in the open literature (Battelle reports). 

Thyroid effects were produced in rats in acute-duration studies at doses as low as 3 mg/kg/day (reduced serum levels of T4 hormone) but not at 1 mg/kg/day, in intermediate-duration studies at doses as low as 0.05 mg/kg/day (increased number and decreased size of follicles), and in chronic-duration studies at doses as low as 1.3 mg/kg/day. The no-observed-adverse-effect level (NOAEL) of 1 mg/kg/day is used herein as the basis for an acute-duration minimal risk level (MRL) for oral exposure. The acute-duration lowest-observed-adverse-effect level (LOAEL) for hepatic effects is identical to the LOAEL for acute thyroid toxicity, but is a less appropriate basis for the MRL because organ functional implications are not as clear. The intermediate-duration LOAELs for thyroid and hepatic effects are also comparable to each other, but neither of these LOAELs are suitable for an intermediate MRL because reproductive and developmental toxicity occurred at a lower dosage. The thyroid LOAEL for chronic-duration exposure is unsuitable for deriving a chronic MRL because decreased survival occurred at the same dose (lower doses were not tested), and thyroid, liver, and other effects occurred at lower doses in intermediate-duration studies. 

IPCS is producing this monograph as a tool for use by public health officials, research and regulatory scientists, and risk assessors. It is intended to complement the monographs, reviews, and test guidelines on reproductive and developmental toxicity currently... 

The reproductive and developmental toxicity data component of the evaluative process determines one or the other of two judgments first, that the collective data are sufficient (or insufficient) to ascribe an adverse effect under specified conditions and second, that the data are sufficient (or insufficient) to conclude that there is no adverse effect under specified conditions. To ensure systematic rigor, the process evaluates the experimental animal data and the human data independently. Each assessment uses a standard format to summarize the conditions of the test (species, dose, route, timing, duration) in which the effect (e.g., decreased sperm count, increased length of estrous cycle, altered sexual dfferentiation of offspring) was or was not observed. 

Once an assessment has determined that the data indicate human risk potential, the next step is to perform a quantitative evaluation. Here, dose-response data from human and animal reproductive and developmental toxicity studies are analyzed to select LOAELs and NOAELs or to calculate a BMD. The assessment should use quantitative human dose-response data if the data span a sufficient range of exposure. Because data on human dose-response relationships are rarely available, the dose-response evaluation is usually based on an assessment of data from tests performed in experimental animals. 

UFs for reproductive and developmental toxicity applied to the NOAEL often include 10-fold factors for interspecies and intraspecies variation. Additional factors might be applied to account for other uncertainties or for additional information that might exist in a database. For example, in circumstances in which only a LOAEL is available, it might be necessary to use an additional UF uncertainty factor of up to 10, depending on the sensitivity of the endpoints evaluated, the adequacy of the tested dose, or general confidence in the LOAEL. An additional uncertainty factor of 3-10 has been used by EPA (1996a) to account for database deficiencies, particularly the lack of reproductive and developmental toxicity studies. 

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