Reproductive and Developmental Toxicity of Phthalates

Abstract

The purposes of this review are to (1) evaluate human and experimental evidence for adverse effects on reproduction and development in humans, produced by exposure to phthalates, and (2) identify knowledge gaps as for future studies. The widespread use of phthalates in consumer products leads to ubiquitous and constant exposure of humans to these chemicals. Phthalates were postulated to produce endocrine-disrupting effects in rodents, where fetal exposure to these compounds was found to induce developmental and reproductive toxicity. The adverse effects observed in rodent models raised concerns as to whether exposure to phthalates represents a potential health risk to humans. At present, di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) have been demonstrated to produce reproductive and developmental toxicity; thus, this review focuses on these chemicals. For the general population, DEHP exposure is predominantly via food. The average concentrations of phthalates are highest in children and decrease with age. At present, DEHP exposures in the general population appear to be close to the tolerable daily intake (TDI), suggesting that at least some individuals exceed the TDI. In addition, specific high-risk groups exist with internal levels that are several orders of magnitude above average. Urinary metabolites used as biomarkers for the internal levels provide additional means to determine more specifically phthalate exposure levels in both general and high-risk populations. However, exposure data are not consistent and there are indications that secondary metabolites may be more accurate indicators of the internal exposure compared to primary metabolites. The present human toxicity data are not sufficient for evaluating the occurrence of reproductive effects following phthalate exposure in humans, based on existing relevant animal data. This is especially the case for data on female reproductive toxicity, which are scarce. Therefore, future research needs to focus on developmental and reproductive endpoints in humans. It should be noted that phthalates occur in mixtures but most toxicological information is based on single compounds. Thus, it is concluded that it is important to improve the knowledge of toxic interactions among the different chemicals and to develop measures for combined exposure to various groups of phthalates.

Environmental contamination with phthalates and its impact on living organisms

“…Phthalates probably contribute to the risk of endometriosis, a disease in which endometrial cells grow outside the uterine cavity. The analyzed compounds also increase the probability of preterm birth [13]. Phthalates were found to be correlated with early sexual maturation in girls [32].…”

“…Phthalates can exert a negative effect on androgens in male infants and contribute to health problems in young boys, including hypospadias (abnormal location of the male external urethral orifice on the ventral side of the penis) and reduced distance between the anus and the genitals [41]. Phthalates can impair sperm function by lowering sperm counts and sperm motility, contributing to sperm defects and increasing the prevalence of DNA damage [13]. An experiment involving 1,040 men in China implicated a correlation between the content of phthalates in urine and sperm and the quality of the latter [40].…”

“…In the work of Lyche [13], DEHP intake with food, expressed in µg/(kg bw · day), was as follows: USA: breastfed infants up to the age of 6 months -7.3 µg, other groups -5 µg, children aged 5-11 years -18.9 µg, adolescents aged 12-19 years -10.0 µg, adults aged 20-70 years -8.2 µg; United Kingdom: infants up to the age of 3 months -13 µg, breastfed infants up to the age of 3 months -21 µg, children aged 3-12 months -8 µg; Germany: subjects aged 14-60 years -2.5-4.3 µg; Denmark: adults -2.7-4.3 µg. The blood concentrations of DEHP metabolites were determined at: USA: newborns -1.30-6.0 µg, pregnant women aged 20-40 years -1.32-9.32 µg, adults aged 20-60 years -0.7-3.6 µg; Germany: children aged 2-14 years -4.3-15.2 µg, students aged 20-29 years -2.7-6.4 µg, subjects aged 14-60 years -2.2-7.7 µg.…”

“…In a study of laboratory rats, phthalates decreased the production of estradiol, a sex hormone responsible for the development of reproductive organs, in females [13]. Exposure to phthalates leads to hormonal and metabolic disorders as well as developmental and reproductive defects resembling testicular dysgenesis in humans [30].…”

“…Phthalates are also linked with increased testis size and lower levels of luteinizing hormone which is responsible for the function of testosterone-producing interstitial cells in the testes. Prolonged exposure to phthalates reduces testosterone production [13,24].…”