Teratogen detection

The detection of a potent dioxin impurity in a major herbicide has focused attention on the nature of chlorinated impurities in pesticides, and in a larger sense, impurities in all chlorinated industrial compounds used extensively in man s environment. The present 2,4,5-T controversy is overshadowed by the dioxin problem. Major disagreement still exists on their relative contributions to the teratogenic effects observed in chicks and the validity of interpretation of high dosage rates used to achieve these effects. We have avoided any assessment of the health-related aspects of dioxins but have dealt almost exclusively with dioxins as an environmental entity. 

Kalter, K. (1977). Correlation between teratogenic and mutagenic effects of chemicals in mammals. In Chemical Mutagens Principles and Methods for Their Detection (Hollanender, A., Ed.). Vol. 6, Plenum Press, New York, pp. 57-82. 

Reproductive toxicity of acesulfame K was studied in test systems aimed at detecting teratogenicity, oral embiyotoxicity and in a multigeneration study. No teratogenicity, no embryotoxicity, and no effects on reproduction, development of the fetuses and lactation performance were found.7... 

Renwick considered that in relation to carcinogenicity for non-genotoxic chemicals and teratogenicity, the application of an extra factor for nature of toxicity is difficult to justify scientifically. He concluded that if a safety factor for nature of toxicity is to be used then logically it should be apphed to the NOAEL for the toxicity, which resulted in its use. For example, in relation to teratogenicity, a factor for nature of toxicity should be applied to the NOAEL for teratogenicity and not for maternal toxicity or some other endpoint. For carcinogenicity, the extra factor should be applied only to the NOAEL for the detection of tumors in those studies where this effect was the rationale for the use of an extra factor. In relation to a steep dose-response, it was concluded that this, in reality, concerns the precision of the NOAEL and therefore relates to the adequacy of the database rather than nature of toxicity. 

Segment 111 peri- and post-natal study. This concentrates on the late part of gestation, not covered by the teratogenicity study, on parturition and on the period of lactation. The study can be particularly useful in detecting subtle effects on the brain, which continues physical and functional development during the foetal and post-natal period, after dosing has ceased in the teratogenicity study. The test animal is usually the rat. 

There is no information on in utero developmental effects in humans exposed to HCB, but oral exposure of young children has caused small or atrophied hands, short stature, pinched facies, osteoporosis of the carpal, metacarpal, and phalangeal bones, and painless arthritic changes. HCB has been demonstrated to cross the placenta in humans and in rodents. HCB residues have been detected in human milk and adipose tissue and in the blood of the umbilical cord of newborn infants and their mothers. Teratogenic effects were not... 

Hexachlorobutadiene did not adversely affect reproduction in animals except at high doses (150 mg/kg/day for 10 weeks). Although there was some evidence of fetotoxicity in animals after inhalation (10 ppm) or oral (15 mg/kg/day) exposure, embryolethality and teratogenicity were not detected. Oral studies in animals indicate that hexachlorobutadiene may increase the risk of renal cancer at dose levels of 20 mg/kg/day. The effects of hexachlorobutadiene are most pronounced after repeated chronic exposure to low doses, suggesting that effects are cumulative. For this reason, there is greater concern for populations living near hazardous waste sites, where exposure to low levels may occur for long periods of time, than for acute exposure scenarios. 

This chapter describes the regulatory toxicology studies required for the reproductive safety evaluation of food additives, with particular attention to the detection of teratogenicity. 

The rabbit is generally the non-rodent species or second species after the rat recommended by the regulatory authorities and is part of the package of regulatory reproductive studies for the detection of potential embryotoxic and/ or teratogenic effects of pharmaceuticals, chemicals, food additives, and other compoimds, including vaccines (see Chapters 1-7). 

It has been reported that embryotoxic or teratogenic effects of some compounds were detected in the New Zealand White rabbit, whereas there was no suspicion of such effects in the rat (2, 3). The origin of these differences between species has remained unelucidated in many cases. However, metabolism, systemic maternal exposure, maternal toxicity, fetal exposure, or placental transfer often explains the discrepancies. 

In the cases where only dose range-finding studies were performed and gave positive results, the routine external examination of the fetuses was supplemented with a detail fresh internal examination for rabbits, or fixed visceral and/or skeletal examinations for rats. These dose range-finding studies were thus sufficiently sensitive to detect strong teratogens. 

In the chemical safety report, the hazard assessment of a particular substance is based on the data set provided in the technical dossier. This contains substance-specific information on physicochemical properties as well as on toxicological and ecotoxicological hazards. One objective of the hazard assessment is the substance s hazard identification, which comprises the determination of its physicochemical and hazardous properties for the purpose of classification. Concerning human health hazards, both human and nonhuman information is taken into consideration and evaluated with respect to the classification criteria laid down in the Dangerous Substances Directive and in the CLP Regulation, respectively. However, in most cases human data do not exist, so the hazard identification has to be based on data from animal experiments. With respect to teratogenicity, this hazardous property may in principle be detected in the following toxicity studies ... 

Although the concept of drug-induced teratogenicity was well established at the time thalidomide was being developed, questions remain today as to whether the effects on embryo-fetal development would have been detected using the standard testing methods. 

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