Low Dose Effects and Timing of Exposures

At a Glance

For many years it was believed that the harmful effects of all toxic chemicals increased with an increasing dose or exposure, and that there was a low threshold dose below which there was no harmful effect. It was also assumed that both adults and children responded similarly to toxic exposures. Scientific evidence now shows that some chemicals, especially endocrine disrupting compounds, can exert negative effects at extremely low levels of exposure, sometimes with more serious or different effects than at higher doses. The timing, duration and pattern of exposure are just as important as the dose. While it’s good to limit exposure to toxic chemicals and radiation at every stage of life, it is even more important during critical periods, including gestation, childhood and pregnancy.

Low Dose Effects

Except in cases of accidental or occupational exposures, most exposures to chemicals are at “very low doses.” Most chemical safety studies look at the toxic effects of higher doses of chemicals and then assume decreasing toxicity with lower doses. Yet substances that disrupt the body’s own hormones — known as endocrine-disrupting compounds (EDCs)—can exert important biological effects at low doses – including those at which they are found in the everyday environment. These effects are often qualitatively different from those found in traditional toxicology experiments. Low-dose effects are especially likely in developing tissues, during the formative periods when even minuscule levels of naturally occurring hormones determine the normal course of development.[1] EDC effects are often strongest at low doses at developmental stages when the complex hormonal regulation has not yet been established.[2]

Prenatal Exposures

A significant and growing body of research shows that pregnant women’s exposure to chemicals—particularly endocrine-disrupting compounds—can increase their children’s risk for breast and other cancers later in life. During fetal development, hormones orchestrate the development of the reproductive and endocrine systems. These systems include breast tissue structure, hormone metabolism and other important factors in breast development.

Prenatal exposures that have been linked to later life breast cancer include diethylstilbestrol (DES), polycyclic aromatic hydrocarbons (PAHs) and bisphenol A (BPA).

Childhood and Adolescence

Today, girls are entering puberty earlier than a generation ago. Data shows that girls get their first periods today, on average, a few months earlier than girls did 40 years ago, and they develop breasts one to two years earlier.[3] This trend may be due to exposures to endocrine-disrupting compounds such as BPA and phthalates[4],[5] before puberty, when the reproductive system, including breast tissue, is extremely sensitive to low levels of estrogens.[6] The younger girls are when they enter puberty, the greater their risk of breast cancer later in life.

Evidence suggests that breast development is sensitive to other exposures, with the strongest evidence for the now-banned pesticide DDT and ionizing radiation from the nuclear bombs in Japan, the accident in Chernobyl and medical radiation treatments.

Pregnancy and Lactation

Human breasts do not fully mature until a woman’s first full-term pregnancy and period of breast-feeding. During this time of rapid cell growth and proliferation, breast cells have heightened sensitivity to the detrimental effects of many environmental exposures. Thus, exposure to toxic chemicals during pregnancy may contribute to increased risks of pregnancy-related breast cancer.[7] The overall rates of pregnancy-associated breast cancer are small, but pregnancy slightly increases risk for several years after delivery, beyond which longer-term protective effects emerge.[8],[9]

For all racial and ethnic groups, having a first child at a younger age and having more kids reduces liftetime breast cancer risk.[10] For black women, though, giving birth at a younger age and having more children increases risk of breast cancer before age 45, and is protective after age 45.[11],[12] The research relating pregnancy to pre-menopausal breast cancer has not explored social, environmental or economic factors that may influence this racial difference in risk. Therefore it is difficult to tease apart which aspects of pregnancy — whether pregnancy-related risks for breast cancer, higher exposure to environmental chemicals during pregnancy or other social factors — determine pre-menopausal risk for the disease.

[1] Vandenberg, L.N., Colborn, T., Hayes, T.B., Heindel, J.J., Jacobs Jr, D.R., Lee, D.H., Shioda, T., Soto, A.M., vom Saal, F.S., Welshons, W.V. and Zoeller, R.T., 2012. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocrine reviews, 33(3), pp.378-455.

[2] Vandenberg, L.N., Colborn, T., Hayes, T.B., Heindel, J.J., Jacobs Jr, D.R., Lee, D.H., Shioda, T., Soto, A.M., vom Saal, F.S., Welshons, W.V. and Zoeller, R.T., 2012. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocrine reviews, 33(3), pp.378-455.

[3] Steingraber, S. (2007). The Falling Age of Puberty in U.S. Girls: What We Know, What we Need to Know. San Francisco: Breast Cancer Fund.

[4] Aksglaede, L., Juul, A., Leffers, H., Skakkebaek, N., & Andersson, A. (2006). The sensitivity of the child to sex steroids: possible impact of exogenous estrogens. Hum Reprod Update, 12, 341–349.

[5] Steingraber, S. (2007). The Falling Age of Puberty in U.S. Girls: What We Know, What we Need to Know. San Francisco: Breast Cancer Fund.

[6] Aksglaede, L., Juul, A., Leffers, H., Skakkebaek, N., & Andersson, A. (2006). The sensitivity of the child to sex steroids: possible impact of exogenous estrogens. Hum Reprod Update, 12, 341–349.

[7] Andersson, T., Johansson, A., Hsieh, C., Cnattingius, S., & Lambe, M. (2009). Increasing incidence of pregnancy-associated breast cancer in Sweden. Obstet Gynecol, 114, 568–572.

[8] Lyons TR, Schedin PJ, Borges VF (2009). Pregnancy and breast cancer: When they collide. J Mamm Gland Biol Neoplasia, 14:87-98.

[9] Russo, J., Moral, R., Wang, R., Russo, I., Lamartiniere, C., & Pereira, J. (2008). Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. J Endocrinol, 196, 101–112.

[10] Kauppila A, Kyyronen P, Hinkula M, Pukkala E (2009). Birth intervals and breast cancer risk. Br J Cancer, 101:1213-1217.

[11] Palmer, J., LA, W., & NJ, H. (2003). Dual effect of parity on breast cancer risk in African-American women. J Natl Cancer Inst, 95, 478–483.

[12] Stuebe, A., Willett, W., Xue, F., & Michels, K. (2009). Lactation and incidence of premenopausal breast cancer: a longitudinal study. Arch Intern Med, 169, 1364–1371.

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