Teratogenic issues

John JA, Wroblewski DJ, Schwetz BA. 1984. Teratogenicity of experimental and occupational exposure to industrial chemicals. Issues and Reviews in Teratology 8 267-324. 

The nature of an effect includes the adversity of the toxicity expressed as the level of and the basis for NOAEL and LOAEL values (Section 4.2.2), and the severity of the specific endpoint or key event (Section 4.2.3), for example judging skin irritation less severe than teratogenicity. An additional assessment factor for severe and/or irreversible effects has been proposed by various groups. This section gives an overview of such proposals and evaluations. Then, the key issues are summarized and our recommendations are presented. 

Since the main intention of the present issue is teratogenicity testing, this chapter will mainly focus on OECD guideline 414 and discuss methodological issues in this context. For a better overview, the remaining Guidelines will be briefly summarized ... 

The main practical implication of this issue is that death of a conceptus can be the result of severe malformations incompatible with viability. Therefore, the often read statement that a compound is embryolethal but not teratogenic is scientifically unsound. 

To illustrate this problem, studies done with fluoxetine are reviewed here in greater detail. This SSRI is perhaps the best studied with regard to the issue of teratogenicity. The reason is related both to its widespread use in women of childbearing potential and to the extended half-life of its active metabolite, norfluoxetine. Even though most physicians will stop medications whenever feasible in a woman who becomes pregnant, the long half-life of norfluoxetine means that it will persist in... 

The issue of lithium-induced dysmorphogenesis is not settled. An earlier report suggested an increase in cardiac anomalies—especially Ebstein s anomaly —in lithium babies, and it is listed as such in Table 59-1 in this book. However, more recent data suggest that lithium carries a relatively low risk of teratogenic effects. Further research is needed in this important area. 

This monograph deals with the practical aspect of teratogens - chemicals which cause birth defects. A special effort has been made to cover such practical issues as how to obtain information about the teratogenic potential of chemicals (Chapter l,by Morgan et al.) I have provided a list of names of... 

Gross MC, Leach W, Prince W, Hoberman A, Barnett J, O Neill C. Embryotoxic and teratogenic evaluation of TNK-tPA in rabbits a study around antigenicity issues. Toxicologist 2000 54(1) 397. 

Evidence of teratogenicity in rats has not been accompanied by reports that it causes harm in human pregnancy, but the WHO recommends avoidance during the first trimester. It is not known if mebendazole enters the breast milk no adverse effects have been reported but the issue has not been specifically studied. 

How then can it be that a compound which has no detectable teratogenic activity in either animal or human studies be held responsible for human congenital malformations The history of Bendectin can be traced to ignorance of the principles of teratology, compounded by precedential case law following the first erroneous decision and to two articles appearing in the popular press. In the September 1979 issue of the National Enquirer, the following was published ... 

Because benzene is nonpolar, it cannot be passed in urine, and will remain in the body until oxidized. Benzene itself is not dangerous to health, but in order to be passed, it is oxidized by cytochrome P-450 in the liver. This produces benzene oxide, a highly teratogenic and carcinogenic compound. Benzene has been replaced by toluene as an industrial solvent, because toluene can be oxidized to benzoic acid, which is mostly harmless to health, and is quickly passed. The decomposition of benzoic acid into benzene and carbon dioxide in soda pop has become an issue recently. 

Jacobson, J.L., and S.W. Jacobson. 1991. Assessment of teratogenic effects on cognitive and behavioral development in infancy and childhood. Pp. 248-261 in Methodological Issues in Controlled Studies on Effects of Prenatal Exposure to Drugs of Abuse, Research Monograph 114, M.M. Kilbey, and K. Asghar, eds. Rockville, MD National Institute on Drug Abuse. 

Radioactive Strontium. Numerous oral exposure have demonstrated the enhanced risk of reproductive effects and cancer in animals exposed to radiostrontium in utero or during lactation. At the higher levels used in injection studies, teratogenic effects were observed on bone development. The possibility of neurological deficits from gestational exposure to radioactive strontium, resulting from radiostrontium incorporation into the cranium and subsequent irradiation of adjacent brain tissue, should be explored. The toxicokinetic and bioavailability issues mentioned in the previous section on Stable Strontium apply to radioactive strontium. Low-level exposure studies should be conducted to evaluate possible impairment of immune function, which results from irradiation of bone marrow by radiostrontium incorporated into bone and which has been observed in animal studies at higher levels. ... 

High proportions of positives are also reported for teratogenic tests. Fully one-third of the 2800 chemicals tested in laboratory animals have been shown to induce birth defects at maximum tolerated doses (5). Thus, it seems likely that a sizeable percentage of both natural and man-made chemicals will be reproductive toxins when tested at the MTD. The world is full of carcinogens and reproductive toxins, and it always has been. The important issue is the human exposure dose, and, fortunately, almost all of these are usually tiny. 

Note A combination with pyridoxine hydrochloride, q.v., has been marketed as Bendeclin for nausea of pregnancy. Prior to 1976, Bendectin also contained dicyclomine. < . v. Discussion of Bendectin and the issue of teratogenicity I. 

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