Reproductive toxicity is a hazard associated with some chemical substances, which interfere in some way with normal reproduction; such substances are called reprotoxic. They may adversely affect sexual function and fertility in adult males and females, as well as causing developmental toxicity in the offspring. Reproductive toxicity is usually defined practically, to include several different effects which are unrelated to each other except in their outcome of lowered effective fertility. The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) separates reproductive toxicity from germ cell mutagenicity and carcinogenicity, even though both these hazards may also affect fertility.
Many drugs can affect the human reproductive system. Their effects can be
- desired (hormonal contraception),
- a minor unwanted side effect (many antidepressants) or
- a major public health problem (thalidomide).
However, most studies of reproductive toxicity have focused on occupational or environmental exposure to chemicals and their effects on reproduction. Both consumption of alcohol and tobacco smoking are known to be "toxic for reproduction" in the sense used here.
One well-known group of substances which are toxic for reproduction are teratogens – substances which cause birth defects. (S)-thalidomide is possibly the most notorious of these. Another group of substances which have received much attention (and prompted some controversy) as possibly toxic for reproduction are the so-called endocrine disruptors. Endocrine disruptors change how hormones are produced and how they interact with their receptors. Endocrine disruptors are classified as estrogenic, anti-estrogenic, androgenic or anti-estrogenic. Each category includes pharmaceutical compounds and environmental compounds. Estrogenic or androgenic compounds will cause the same hormonal responses as the sex steroids (estrogen and testosterone). However anti-estrogenic and anti-andogenic compounds bind to a receptor and block the hormones from binding to their receptors, thus preventing their function. A few examples of the many types of endocrine disruptors are trenbolone (androgenic), flutamide (anti-androgenic), dieththylstilbestrol (estrogenic), Bisphenol A (estrogenic), tributyltin (anti-estrogenic). However, many substances which are toxic for reproduction do not fall into any of these groups: lead compounds, for example, are considered to be toxic for reproduction given their adverse effects on the normal intellectual and psychomotor development of human babies and children.
Bisphenol A (BPA) is an example of an endocrine disruptor which negatively affects reproductive development. BPA is a known as an estrogen mimicker (Xenoestrogen) and a likely androgen mimicker. It is used in the production of various plastic products. BPA exposure in fetal female rats leads to mammary gland morphogenesis, increased formation of ovarian tumors, and increased risk of developing mammary gland neoplasia in adult life.
BPA also affects male fertility by resulting in lower sperm quality and sex function.
Lead is a heavy metal that has been associated not only with mental deficits, but also with male infertility and male reproductive issues. Lead is believed to predominantly affect male reproduction by the disruption of hormones, which reduces the quantity of sperm production in the seminiferous tubules. It has also been proposed that lead causes poor semen quality by increasing reactive oxygen species[clarification needed] due to lipid peroxidation, leading to cellular damage.
Other reproductive toxins such as Thalidomide were once prescribed therapeutically. In the 1950s and early 1960s, Thalidomide was widely used in Europe as an anti-nausea medication to alleviate morning sickness in pregnant women. But it was found in the 1960s that Thalidomide altered embryo development and led to limb deformities such as thumb absence, underdevelopment of entire limbs, or phocomelia. Thalidomide may have caused teratogenic effects in over 10,000 babies worldwide.
Diethylstilbestrol (DES), a synthetic estrogen known to be another reproductive toxin, was used from 1938 to 1971 to prevent spontaneous abortions. DES causes cancer and mutations by producing highly reactive metabolites, also causing DNA adducts to form. Exposure to DES in the womb can cause atypical reproductive tract formation. Specifically, females exposed, in utero, to DES during the first trimester have are more likely to develop clear cell vaginal carcinoma, and males have an increased risk of hypospadias.
- Annex I, section 3.7, Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJEC, L353, 31.12.2008, pp. 1–1355, at pp. 107–14.
- Part 3, chapter 3.7, Globally Harmonized System of Classification and Labelling of Chemicals (Second revised ed.), New York and Geneva: United Nations, 2007, pp. 175–86, ISBN 978-92-1-116957-7, ST/SG/AC.10/30/Rev.2.
- International Programme on Chemical Safety (2001). "Principles For Evaluating Health Risks To Reproduction Associated With Exposure To Chemicals". Environmental Health Criteria. Geneva: World Health Organization. 225.
- International Programme on Chemical Safety (2002). "Global assessment of the state-of-the-science of endocrine disruptors". Geneva: World Health Organization. WHO/PCS/EDC/02.2
- Commission Directive 2004/73/EC of 29 August 2004 adapting to technical progress for the 29th time Council Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. OJEC L152, 30.04.2004, pp. 1–311 (index no. 082-001-00-6).
- Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJEC L353, 31.12.2008, pp. 1–1355 at p. 444 (index no. 082-001-00-6).
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- Helen Klip, MPH, Janneke Verloop, MSc, Jan D van Gool, MD, Marlies ETA Koster, MSc, Prof Curt W Burger, MD, Prof Flora E van Leeuwen, MD, for the OMEGA project group.(2002, March 30) Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. The Lancet. 359(9312), 1102-1107.