Spacecraft Water Exposure Guidelines for Selected Contaminants Volume 1 (2004) / Chapter Skim
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Appendix 4: Di(2-ethylhexyl) Phthalate
Appendix 4: Di(2-ethylhexyl) Phthalate
Pages 121-168
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From page 121... ...
. Oral exposure ofthe general population, 121
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From page 122... ...
TOXICOKINETICS Primary targets for DEHP toxicity are the liver and testes. Effects in the pituitary, thyroid, ovaries, andblood have also been explored.
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The toxicokinetic discussion will focus on the relevance of DEHP's carcinogenic and reproductive effects in rodents to human health. The toxicokinetics of DEHP are remarkably complex and depend on many different factors.
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From page 124... ...
These quantitative metabolic differences may help explain the interspecies differences in peroxisome proliferation (PP) and in the induction of cancer; however, the data are not completely consistent in implicating specific metabolites.
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From page 125... ...
MEHP is hydrolyzed to phthalic acid by enzymes in liver microsomes and is found free in the urine of rodents; hamsters and mice excrete more than rats or guinea pigs (Albro et al. 1982; Albro 1986~.
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Using cultured rat hepatocytes and an enzymatic marker of PP, Mitchell et al.
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, adapted from two figures in Holden and Tugwood (1999) , modeling how the interspecies differences in PP susceptibility can be understood.
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From page 128... ...
Metabolites 2EH and 2EHA have been shown to produce developmental toxicity in multiple rodent species, but the reproductive effects ofthose metabolites is less well characterized (NIP 2000~. Phthalic acid has also been shown to be a developmental toxicant in rodents but is less potent than other tested metabolites (NIP 2000~.
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From page 129... ...
For example, only oral studies with a feeding or water protocol were considered, unless only other types of studies were available for a given exposure time or could demonstrate relevant species differences in susceptibility. Oral gavage studies tend to exaggerate the toxic effect of a compound because of the bolus nature ofthe dose.
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From page 130... ...
Other oral LD50s have been derived from unpublished data from Union Carbide and include the following: guinea pigs, 26,000 mg/kg; rats, 34,000 mg/kg; and mice, 34,000 mg/kg (Krauskopf 1973~. Those LD50 values place the acute toxicity of DEHP below that of smaller dialkyl phthalates and above that of larger dialkyl phthalates (Krauskopf 1973~.
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From page 131... ...
Observations of toxic effects in this range of exposure times are often made as interim observations during a much longer study. At 2 wk into a 79 wk study, male Wistar rats given DEHP at 2% in their food showed a 60% increase in liver weights and induction of enzymes associated with PP and hydrogen peroxide metabolism (assessed first at 4 wk)
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From page 132... ...
Various enzymes from liver tissue showed different activities from controls at various times after the doses, but the bile canalicular damage seen in male rats at 3 ~ was gone at 7 d. Based on the increases in liver weights, which were transient at 7-28 ~ in males exposed at the lowest dose, one can conclude that 50 mg/kg/d produces a marginal adverse effect.
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From page 133... ...
(1985b) , this study suggests that in mature rats liver effects occur at much lower doses than do male reproductive effects.
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From page 134... ...
The database includes evidence that DEHP is a reproductive toxicant in male rats, mice, guinea pigs, and ferrets and produces structural changes in the testes, reduced fertility, and altered sperm dysfunction (NTP 2000~. Morphologic, functional, end biochemical assessment has shown that the Sertoli cells are cellular targets for adult and pre-adult exposures (NTP 2000~.
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From page 135... ...
1986~. According to a recent risk assessment on reproductive toxicity, "Absorption studies, as well as PBPK modeling, suggest that DEHP metabolism to MEHP and its absorption from the human gut and marmoset gut saturates at a low dose relative to that ofthe rat" (NIP 2000~.
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From page 136... ...
Despite a few irregularities in the study (e.g., lung infections causing excess mortality in control rats, problems with an unusually high number of litters in For control rats, and liver-weight increases in female guinea pigs that were not doserelated) , the authors concluded that the three species are roughly comparable in sensitivity to production of neoplastic lesions following DEHP ingestion, with a NOAEL of 0.06 g/kg/d or higher (Carpenter et al.
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From page 137... ...
and seminiferous tubular degeneration ofthe testis was found in 43 of 48 high-dose male rats (one of 49 controls)
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From page 138... ...
. An in vitro study using cultured kidney cells showed that when cells are exposed to MEHP or 2-ethy~hexanoic acid, only the former causes a marked toxic effect (Rothenbacher et al.
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From page 139... ...
2000~. The pertinent data and the BMD analysis for reduced red blood cell (RBC)
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From page 140... ...
The increases were significant when compared either pair-wise with controls or by a trend test. It is interesting that, in male rats, ingestion of DEHP caused a signif~cant reduction in the incidence of neoplasms of the pituitary, thyroid, and testes.
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From page 141... ...
did not cause increased liver weights, induce PP, or induce an increased incidence of liver tumors. The authors concluded that a threshold approach to calculating the no-significant-risk dose for human exposure is appropriate (David et al.
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From page 142... ...
The goal of this section is to select representative reports in each of the areas of testing and place the overall results into the context of our understanding of the way DEHP induces liver tumors in rodents. The vast majority of bacterial mutagenicity studies have been negative for DEHP and its metabolites, MEHP, 2-ethy~hexanol, and phthalic acid.
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From page 143... ...
1985~. In viva studies of rat liver from animals exposed to oral doses of DEHP have likewise been negative.
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From page 145... ...
However, young male rats are much more susceptible to DEHP testicular injury than are mature rats. For example, in 4-wk-old rats given a 1 0-d oral treatment of DEHP at 2,800 mglkg/d, testes, seminal vesicles, end prostates weighed approximately 50°/O less than the same organs in control rats (Gray and Gangolli 1986~.
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From page 146... ...
After reviewing the literature on DEHP-induced testicular atrophy, it was concluded that rats and guinea pigs are the most susceptible to testicular damage, mice are intermediate in susceptibility, and marmosets and hamsters are least susceptible (WHO 1992~. There has been much less study devoted to female reproductive toxicity then to male reproductive toxicity.
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From page 147... ...
MEHP, the presumptive active metabolite of DEHP, inhibits FSHstimulated cAMP accumulation in both Sertoli cells and in granulosa cells. The endocrine and paracine support granulosa cells provide to the developing ovum is analogous to the role Sertoli cells play for developing spermatozoa.
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From page 148... ...
One investigator reported a 9°/0 average decrease in RBC count in male rats ingesting DEHP at 5,000 ppm for 13 wk (Poon et al.
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From page 149... ...
149 ·_I Cal ·_I o Em C)
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lo lo lo .O ~ ~ ~ .
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From page 153... ...
153 X I\ en, ~ c Ct Cd Cal ~ _, · ~ ~ at 3 3 ~ =¢ =¢ =¢ so so C)
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From page 154... ...
In a document entitled "Final Drinking Water Criteria Document for Phthalic Acid Esters" (EPA 1992b) , an interim value was indicated on the basis of the most sensitive slope of the tumor incidence from the data of Kluwe et al.
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From page 155... ...
1953~. From the guinea pig study, 19 mg/kg/d was determined to be a LOAEL for increases in liver weights in females.
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From page 156... ...
RATIONALE Setting specific human exposure limits for DEHP is difficult because although there is a plethora of data in rodents, sufficient mechanistic data suggest that significant interspecies differences affect the extrapolation of risk to human health. Recent data on the incidence of liver tumors in rats and mice suggest that a linear model ofthe log-dose vs risk, which was used by EPA (1992)
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From page 157... ...
A risk assessment will also be done for chronic renal inflammation seen in male mice (Kluwe et al. 1982~; however, renal toxicity seen in male rats will not be used for risk assessment.
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From page 158... ...
For male reproductive effects, the weight of evidence suggests that adult humans are much less susceptible than rodents to DEHP; therefore, the usual species extrapolation factor of 10 was reduced to 3. Ingestion For 100 d The ACs for this time of exposure were set to avoid potential testicular injury and hematotoxicity on the basis of the results of Poon et al.
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From page 159... ...
= 30 mg/L. The factors of 10,3, and 1.1 are for interspecies differences, spaceflight effects, and time differences between rat exposures and potential human exposures, respectively.
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From page 160... ...
Clearly, the kidney is not very sensitive to oral ingestion of DEHP. Functional Reproductive Toxicity Aside from the testicular atrophy caused in rodents by DEHP ingestion, a functional impairment has been demonstrated in mice (Meinick et al.
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From page 161... ...
161 o .$ o v ¢ Cal o C)
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From page 162... ...
162 5 A V o .$ o V ¢ Cat o C)
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From page 163... ...
In particular, exposure during early development presents a special concern for male reproductive toxicity. However, the purpose ofthis document is to evaluate relevant risks for occupational exposures for adult, nonpregnant astronauts.
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From page 164... ...
phthalate for rats, guinea pigs, and dogs.
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From page 165... ...
1992b. Drinking Water Criteria Document for Phthalic Acid Esters (Final)
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From page 166... ...
1988. Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity ofthe peroxisome proliferators di(2-ethylhexyl)
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From page 167... ...
2000. Methods for Developing Spacecraft Water Exposure Guidelines.
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From page 168... ...
Developmental toxicity evaluation of dietary di(2-ethylhexyl) phthalate in Fischer 344 rats and CD-1 mice.
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