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Cadmium & Women’s Health

iStock-483116645Evidence for an additional disease burden associated with the toxic metal cadmium was recently published in the journal Human Reproduction. This study used cross-sectional data from a nationally representative sample, 4 cycles from the National Health and Nutrition Examination Survey (NHANES) 1999–2006, and included 1,647 women aged 20-54. Endometriosis is thought to affect approximately 10% of reproductive-age women, with a weighted prevalence of 9.4% of women diagnosed by survey in this study. Spot urinary cadmium levels were checked, with several corrections based upon the year of analysis, such as correcting for molybdenum oxide in the 1999-2002 NHANES cycle. Urinary cadmium is considered to be a biomarker for long-term cadmium exposure (in contrast to blood cadmium), between 10-30 years, as it is efficiently retained in the kidneys.

Compared to women in the lowest quartile of urinary cadmium (<0.15 ng/mL), women in every other quartile had an increased risk for endometriosis. After multivariate adjustment, women in the 2nd and 3rd quartile (0.15=<0.23 and 0.15=<0.23 ng/mL, respectively) had a doubling in their risk, while women in the 4th quartile (≥0.38 ng/mL) had a 60% greater risk. Even more concerning, when the analysis was restricted to women that did not have a history of menopause, hysterectomy, or bilateral oophorectomy, the risk was even greater, ranging from a 140 to 200% increase.

The authors report that the observed association between endometriosis and cadmium exposure is biologically plausible, as cadmium may be considered a metalloestrogen, demonstrating estrogenic effects on breast cancer cells, estrogen receptors, etc., and may promote the development and progression of ectopic endometriotic lesions thought to drive the disease process. This estrogenic effect may also explain why women in the highest quartile of cadmium exposure had a lower risk than women in the middle quartiles (though still higher than women in the lowest quartile), as there is likely to be a threshold for harm once estrogen receptors are saturated (and may be downregulated in response). The authors also suggest that other conditions which have been linked to cadmium exposure may also mediate the connection between cadmium and endometriosis, including polycystic ovary syndrome, infertility, adenomyosis, and pregnancy loss, and that cadmium may be only indirectly responsible. It is also possible that tobacco smoking may be a confounder, as it is an important source of cadmium exposure; however, sensitivity analyses among “never smokers” still point to an increased risk, though of a somewhat smaller magnitude.

As mentioned above, cadmium exposure may pose multiple threats, particularly to women. Results of a prospective cohort study published in Environment International also examined the risk between urinary cadmium levels and several disease outcomes, including fractures, cardiovascular disease, and overall mortality. Over 4,000 women between the ages of 56-85 had, on average, 11 years of follow-up. The study found a 20% increase in risk for fractures and a 38% increase in risk for all-cause mortality when comparing the highest to lowest quartiles, risks that were similar in smokers and never smokers. It’s important to note that these risks were observed at levels of cadmium exposure that are quite common. Additionally, given how widespread cadmium exposure is, it’s difficult to find a “cadmium-free” population to estimate relative risk. When everyone has low-level cadmium exposure, an increase in risk can be difficult to spot.

The risk for osteoporosis associated with cadmium exposure emphasizes this last point. In a recently published systematic review and meta-analysis, the risk for osteoporosis was estimated among women with low cadmium exposure (defined as urinary cadmium ≥ 0.5 versus < 0.5 μg/g creatinine) as well as women with high cadmium exposure (≥ 5 versus < 5 μg/g creatinine). This analysis included nearly 8,000 women age 50+ from studies around the world, and found that for women with low cadmium exposure, the risk for osteoporosis was 95% higher. For women with high cadmium exposure, the risk was 99% higher. Overall, this suggests that even at low levels of exposure, the impact on bone health is substantial.

To drive home how consequential cadmium exposure is to bone health, the one study based in the U.S. (included in the meta-analysis above) was published in Environmental Health Perspectives in 2008. This study also used NHANES data over two different time periods, and estimated the risk for osteoporosis among women with “low” cadmium exposure, i.e., they compared urinary levels between 0.50 and 1.00 to those with ≤ 0.50 μg/g creatinine. Even at this low level of exposure, there was a 43% greater risk for osteoporosis observed. Importantly, smoking did not modify this risk, indicating that dietary cadmium was responsible for the increase in risk.

But easy to overlook in this study was a brief calculation and statement found only in the conclusion. The vast majority of women in the U.S., 73%, have urinary cadmium levels associated with increased risk (> 0.50 μg/g creatinine). Using this prevalence and the excess risk attributed to cadmium, the authors calculated the “population attributable fraction” of osteoporosis due to cadmium. This is the portion of a disease associated with a specific risk factor, which in theory would disappear if the risk factor were eliminated. In this case, they calculated it to be 21%. In other words, 21% of osteoporosis may dissolve if women were not exposed to cadmium at even these low levels.

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