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Epidemiology:
doi: 10.1097/01.EDE.0000066304.10469.4F
Commentaries

Male Reproductive Effects of Phthalates: An Emerging Picture

Hoppin, Jane A.

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From the Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC.

Address correspondence to: Jane A. Hoppin, Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, PO Box 12233, MD A3-05, Research Triangle Park, NC 27709; hoppin1@niehs.nih.gov.

Like so many other byproducts of human enterprise, phthalates, without much attention paid to their possible health effects, have become widely distributed among people. In 2000, the Centers for Disease Control and Prevention (CDC) published the first data on phthalate levels in the U.S. population. The highest levels were still less than 1% of the lowest observable effect level in animals, though limited human health data were available. 1,2 However, three recent reports 3–5 (including one in this issue of Epidemiology by Susan Duty and colleagues 3) suggest that phthalates at current population levels may have measurable effects on male reproductive health.

“…there is an emerging pattern of adverse semen parameters in the presence of high phthalate levels.”

Just as “plastics” was the key word of advice to Dustin Hoffman in The Graduate, “phthalates” may become the key word for environmental epidemiologists in coming years. Phthalate esters are common in PVC plastics, paints and cosmetics. Exposure of laboratory animals as fetuses, pups and adults to phthalate esters can cause reproductive harm. In 1999, the U.S. National Toxicology Program commissioned an expert panel to assess seven phthalate esters and their risk to human reproduction. The candidates included two prime suspects: DEHP (diethylhexyl phthalate) and DBP (dibutyl phthalate). The primary metabolite of DEHP is MEHP (monoethylhexyl phthalate), an antiandrogen that disrupts male reproductive development in animals. Based on the limited scientific literature, which 2 years ago included virtually no human data, the panel identified “serious concern” for neonatal males exposed to DEHP. 6

Preterm babies are highly exposed to DEHP via intravenous and other medical tubing. 7 If phthalates damage male reproduction, preterm male infants are a group likely to experience problems. However, the ability to evaluate this group is limited. It is difficult to assemble a comparison group for a group of infants having extensive medical interventions. Although this remains a vital research question, we will have to look elsewhere for clues about potential reproductive damage from phthalates.

In 2000, the CDC released the first population-based data on phthalate exposure. Four phthalate monoesters, including MEHP and MBP (the primary metabolite of DBP), were detectable in nearly all 289 people in an NHANES III sample from 1988–1994 2 and in most of the 1029 people from the NHANES data of 1999. 8 By far the highest levels were for monoethyl phthalate (MEP), a chemical not evaluated by the National Toxicology Program because of its apparent low toxicity in laboratory animals.

The extent of human exposure is troubling. Detectable exposures range over two orders of magnitude, and there are practically no data on possible human health effects. In the past few months, the first results from epidemiologic studies have become available. 4–5 It appears that the reproductive effects of phthalates may not be limited to highly exposed animals. In studies from infertility clinics in India 4 and Boston, 5 there is an emerging pattern of adverse semen parameters in the presence of high phthalate levels.

“Researchers…should not neglect the possibility that phthalates might affect women as well.”

In India, Rozati and colleagues 4 measured phthalate levels in seminal fluid of community controls and patients being treated at an infertility clinic. Phthalates were associated with adverse morphology, sperm head defects and a higher percentage of single-strand deoxyribonucleic acid (DNA) in sperm. These authors used a measure of total phthalate diesters, which does not permit the responsible agent to be specifically identified. Because the treatment protocol was not mentioned, it is possible that these patients may have been exposed to specific phthalates in the course of their medical treatment. If the patients had the same pattern of phthalate exposure as the U.S. population, the main phthalate would be MEP. Among men at a Boston infertility clinic, urinary levels of MEP, but not other phthalates, were associated with adverse integrity of sperm DNA. 5 Although MEP is not known to be genotoxic, 9 taken together these studies suggest the need for further research into its potential to cause DNA damage in sperm.

In this issue, Susan Duty and colleagues 3 provide further evidence from the Boston study of infertile men. This new paper reports an association of high urinary MBP levels with low sperm concentration and sperm motility. There was a similar association between MBzP (monobenzylphthalate) and sperm concentration. Surprisingly, no association was observed with MEHP, the phthalate of most concern in the report from the expert panel.

Perhaps this is not so unexpected. As the authors note, 3 the animal literature suggests that DEHP (with its metabolite MEHP) has its effects on the male reproductive system only when exposure is before birth. DEHP exposure later in life apparently has no effect. 6 In contrast, DBP can apparently disrupt male reproduction at all stages of life. Thus, the apparent association of MBP (DBP’s active metabolite) with low sperm count and motility in humans is not implausible.

Even so, these are all preliminary findings. These studies have been carried out within selected groups of men with known or suspected fertility problems. Both of the analyses by Duty 3,7 have been conducted among men from subfertile couples, so the spectrum of infertility represented is broader than among participants in the study by Rozati, 6 in which all cases had documented low sperm counts. All three studies relied on one sperm sample and one phthalate sample from each subject. As Duty notes, “an accurate measurement of sperm count is difficult using one specimen.” Although urinary phthalate levels appear reproducible from one day to the next, 10 no data are available to assess the long-term reliability of these urinary measures with a short half-life. The stage is now set for more detailed and comprehensive studies of men who are more representative of the general population.

Finally, we should not overlook the fact that MBP levels are higher in women than men, 2 perhaps owing to exposures through cosmetics. The animal data suggest that phthalates can also have reproductive effects in females, including impaired uterine function. 11 As researchers attempt to replicate Duty’s findings in men, they should not neglect the possibility that phthalates might affect women as well.

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About the Author

JANE HOPPIN is an environmental epidemiologist at the National Institute of Environmental Health Sciences of the National Institutes of Health. She has conducted studies on the health effects of lead and pesticides. Her current work includes the investigation of human exposure to phthalates, particularly with respect to patterns of exposure.

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References

1. Mylchreest E, Sar M, Wallace DG, Foster PM. Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate. Reprod Toxicol 2002; 16: 19–28.

2. Blount BC, Silva MJ, Caudill SP, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000; 108: 979–982.

3. Duty SM, Silva MJ, Barr DB, et al. Phthalate exposure and human semen parameters. Epidemiology 2003; 14: 269–277.

4. Rozati R, Reddy PP, Reddanna P, Mujtaba R. Role of environmental estrogens in the deterioration of male factor fertility. Fertil Steril 2002; 78: 1187–1194.

5. Duty S, Singh N, Silva M, et al. The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect: doi:10.1289/ehp.5756. Available at: http://dx.doi.org./ Accessed 6 December 2002.

6. Center for the Evaluation of Risks to Human Reproduction (CERHR). NTP-CERHR Expert Panel Report on Di(2-ethylhexyl) Phthalate. Research Triangle Park, NC: National Toxicology Program, U.S. Department of Health and Human Services, 2000.

7. Loff S, Kabs F, Witt K, Sartoris J, Mandl B, Niessen KH, Waag KL. Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pediatr Surg 2000; 35: 1775–1781.

8. Centers for Disease Control and Prevention (CDC). National Report on Human Exposure to Environmental Chemicals. Atlanta: CDC, 2001.

9. Api AM. Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients. Food Chemical Toxicol 2001; 39: 97–108.

10. Hoppin JA, Brock JW, Davis BJ, Baird DD. Reproducibility of urinary phthalate metabolites in first morning urine samples. Environ Health Perspect 2002; 110: 515–518.

11. Ema M, Miyawaki E. Effects of monobutyl phthalate on reproductive function in pregnant and pseudopregnant rats. Reprod Toxicol 2001; 15: 261–267.

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