Phthalates and Cumulative Risk Assessment The Tasks Ahead (2008) / Chapter Skim
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3 Toxicity Assessment
3 Toxicity Assessment
Pages 39-67
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From page 39... ...
Aspects of the phthalate syndrome -- its relationship to the hypothesized human testicular dysgenesis syndrome, structure-activity relationships, and mechanisms of action -- are described next. Agents that produce effects on reproductive development similar to those of phthalates are noted.
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From page 40... ...
is under androgen control. Because the majority of studies discussed below were conducted in rats, it is helpful to compare the rat and human developmental periods for male sexual differentiation (see Figure 3-2)
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From page 41... ...
Given the above discussion, it is clear that normal differentiation of the male phenotype has specific requirements for fetal testicular hormones, including androgens, and therefore can be particularly sensitive to the action of environmental agents that can alter the endocrine milieu of the fetal testis during critical periods of development.
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From page 42... ...
EARLY TERATOLOGY FINDINGS The early studies that examined the potential for phthalate exposure to cause adverse effects on fetal development were standard teratology studies, in which pregnant animals were exposed during GD 6-15, and the offspring were examined just before birth, when the reproductive tract is immature. Generally, the concentration of a phthalate required to cause developmental toxicity in those studies was relatively high, and maternal toxicity was typically observed (NTP 2000, 2003a,b,c,d,e,f, 2006)
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From page 43... ...
1987) indicated that the Sertoli cell was the initial testicular target and that loss of support of the germ cells resulted in their rapid sloughing into the seminiferous tubular lumen, which resulted in a spermatogenic stage-specific lesion in adult animals.
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From page 44... ...
Although that does not imply that all agents known to produce injury in the rat would cause toxicity in humans, it does suggest that the rat is generally a good model of human male reproductive toxicity. The ability of specific phthalates to alter reproductive development in utero was first demonstrated by a multigeneration study of DBP in the rat by NTP (NTP 1991; Wine et al.
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From page 45... ...
Studies have shown that male rats exposed to biologically active phthalates in utero during the period of sexual differentiation exhibit a number of reproductive tract abnormalities, which may include underdeveloped or absent reproductive organs, malformed external genitalia (hypospadias) , undescended testes (cryptorchidism)
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From page 46... ...
FIGURE 3-3 Effect of DBP given over 3 days on reproductive tract malformations. Pregnant Sprague-Dawley rats were given DBP on GD 15-17, critical window for induction of phthalate syndrome, at 0, 250, 500, or 750 mg/kg-d by gavage in corn oil (5 mL/kg-d)
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From page 47... ...
TABLE 3-2 Comparison of Human Male Reproductive Effects of Concern with Effects of in Utero Phthalate Exposure in Rats Human Reproductive Effects with a Effects of in Utero Phthalate Possible in Utero Origin Exposure in Rats Infertility √ Decreased sperm count √ Cryptorchidism √ Reproductive tract malformations √ Hypospadias √ Testicular tumorsa √a a Testicular tumors in rats are Leydig-cell-derived, not germ-cell-derived as in humans. 2 There is some uncertainty in the rates reported, which depend on diagnostic criteria and on the time at which evaluation is conducted.
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From page 48... ...
Mechanism of Action The primary target of phthalates after in utero exposure is the fetal testis. One of the earliest phthalate-related fetal effects observed in rats was disturbance of fetal testicular Leydig cell function or development (Parks et al.
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From page 49... ...
Separately from effects on testosterone synthesis, in utero phthalate exposure disrupts seminiferous cord formation and germ-cell development and leads to the appearance of large multinucleated germ cells in late gestation (Mylchreest et al. 2002; Barlow and Foster 2003; Kleymenova et al.
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There has, however, been one report of effects on developing testicular Leydig cells and decreased testosterone concentrations in the neonatal marmoset (Hallmark et al.
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. AGENTS THAT PRODUCE SIMILAR EFFECTS ON REPRODUCTIVE DEVELOPMENT Although the spectrum of effects of some phthalates on male reproductive development in utero in rats is specific (the phthalate syndrome)
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Figure 3-5 shows the relationship between the phthalate syndrome and the androgen-insufficiency effects and compares the phthalate syndrome noted in rats with the hypothesized human testicular dysgenesis syndrome. There is a remarkable overlap in response between the phthalate syndrome and the hypothesized human testicular dysgenesis syndrome, except for responses for which rats are sexually dimorphic (retention of nipples)
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From page 53... ...
↓Fertility ↓insl3 Gubernacular malformations FIGURE 3-5 Relationship of phthalate syndrome in rats to that noted for agents that perturb androgen action to produce androgen insufficiency and to the hypothesized testicular dysgenesis syndrome in humans. End points in brackets are restricted to findings in experimental animals.
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From page 54... ...
Finasteride is a classic example of a drug in this class; when administered in utero to dams during the period of male sexual differentiation, it can produce a wide array of male reproductive tract malformations (see, for example, Bowman et al.
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From page 55... ...
TABLE 3-4 Effects of Agents That Can Produce Androgen Insufficiency by Different Pharmacologic Activities or Mechanisms and the Most Common Resulting Malformation after in Utero Exposure of Pregnant Rats during Sexual Differentiation ↓Androgen- ↓Testosterone or Most Commonly Receptor ↓Insl3 Dihydrotestosterone Observed Agent Activity Activity Concentrations Malformations Vinclozolin, + – – Hypospadias Procymidone, Flutamide Linuron + – + Epididymal and testicular abnormalities No gubernacular agenesis Prochloraz + – + Hypospadias Finasteride – – + Hypospadias DBP, DIBP, – + + Epididymal and BBP, DPP, testicular DEHP, DIHP, abnormalities DINP, DCHP Gubernacular agenesis DEP, DMP – – – No malformations noted +, known pharmacologic activity; –, no activity.
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From page 56... ...
. TABLE 3-5 Summary of Hepatocarcinogenic Effects of Phthalates Species Sex NOEL LOEL Reference (mg/kg-d)
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. BBP causes hepatic cancer and pancreatic acinar-cell tumors but not Leydig cell tumors (NTP 1997)
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. As noted previously and illustrated in Figure 3-5, the phthalate syndrome observed in rats has parallels with the hypothesized human testicular dysgenesis syndrome (Sharpe 2001; Fisher et al.
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From page 59... ...
2004. Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl)
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2005. Mode of action: Impaired fetal Leydig cell function-effects on male reproductive development produced by certain phthalate esters.
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2004. A mixture of the "antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fash ion.
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2004. Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl)
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2002a. Male rats exposed to linuron in utero exhibit permanent changes in anogenital distance, nipple retention, and epididymal malformations that result in subsequent testicular atrophy.
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2003a. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Butyl Benzyl Phthalate (BBP)
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2000. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat.
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From page 66... ...
2008. An Animal Model for "Testicular Dysgenesis Syndrome" Based on in Utero Exposure to Dibutyl Phthalate (DBP)
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From page 67... ...
2005. Decrease in anogenital distance among male infants with prenatal phthalate exposure.
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