Fischer-344 rats treated with 12,500 ppm (728 and 879 mg/kg/d for male and females, respectively) and B6C3F1 mice treated with 6,000 ppm (1,227 and 1,408 mg/kg/d, respectively) di(2-ethylhexyl)phthalate (DEHP) in the diet for 78 weeks were allowed to recover for an additional 26 weeks on control diet. Blood was analyzed at weeks 78 and 104 from 10 animals per sex per group; animals were sacrificed at weeks 79 and 105 for histopathologic examination. The results are compared with data from animals continuously exposed to these dietary levels for 104 weeks (10, 11). Body weights and food consumption were measured monthly. BUN, albumin, and globulin that were significantly different for rats exposed to DEHP throughout 104 weeks, were comparable to controls for the recovery group. Reversibility of chronic effects on erythrocyte count, hemoglobin, and hematocrit values was apparent only for female rats. Chronic exposure demonstrated effects on liver, kidney, and testes weights. All organ weight effects except for testes for the Recovery group of rats, and all organ weight effects for mice, were reversible. Pigmentation of Kupffer cells and renal tubules present in chronically treated rats were not observed for the Recovery group. Lesions in the testes and pituitary gland were not reversible in rats. This may be a reflection of the senescence of the hypothalamic-gona d axis in rats. Cessation of exposure for mice resulted in amelioration of effects in the kidneys, liver, and testes. The extent of reversibility suggests that many chronic effects may be associated with a metabolic phenomenon such as peroxisome proliferation, which also reverted to control levels after 26 weeks of recovery.
Agarwal DK, Eustis S., Lamb JC, Reel JR, Kluwe WM (1986). Effects of di(2-ethylhexyl)phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats . Environ Health Perspect65:343—350.
2.
Alison RH, Capen CC, Prentice DE (1994). Neoplastic lesions of questionable significance to humans. Toxicol Pathol22: 179—186.
3.
Braissant O. , Foufele F., Scotto C., Dauca M., Wahli W. (1996). Differential expression of peroxisome proliferator-activated receptors: tissue distribution of PPARα, β and γ in the adult rat. Endocrinology137: 354—366.
4.
Caldwell DJ, Eldridge SR, Lington AW, McKee RH (1999). Retrospective evaluation of alpha 2u globulin accumulation in male rat kidneys following high doses of diisononyl phthalate . Toxicol Sci51: 153—160.
5.
Casey HW, Ayers KM, Robinson FR (1978). The urinary system. In: Pathology of Laboratory Animals, Benirschke K, Garner FM, Jones TC (eds). Springer-Verlag, New York, pp 142—145.
6.
Chawla A., Schwarz EJ, Dimaculangan DD, Lazar MA (1994). Peroxisome proliferator-activate d receptor (PPAR) γ : Adipose-predominan texpression and induction early in adipocyte differentiation . Endocrinology135: 798— 800.
7.
Curto KA (1983). Effects of di-(2-ethylhexyl)phthalate and mono-ethylhexyl phthalate on male rodent gonad. Ph.D. Dissertation, West Virginia University, Morgantown, West Virginia.
8.
Daughtrey WC (1994). Criteria for determining neurotoxicity. Neurobehavioral Toxicity: Analysis and Interpretation, Weiss B, O'Donoghue J (eds). Raven Press, Ltd., New York.
9.
David RM, Moore MR, Cifone MA, Finney DC, Guest D. (1999). Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesi s of di(2-ethylhexyl)phthalate and the effects of recovery. Toxicol Sci50: 195—205.
10.
David RM, Moore MR, Finney DC, Guest D. (2000a). Chronic toxicity of di(2-ethylhexyl)phthalate in rats. Toxicol Sci55: 433—443.
11.
David RM, Moore MR, Finney DC, Guest D. (2000b). Chronic toxicity of di(2-ethylhexyl)phthalate in mice. Toxicol Sci58: 377—385.
12.
Dirven Haam , Van Den Broek PHH, Peeters MCE, Peters JGP, Mennes WC, Blaauboer BJ, Noordhoek J., Jongeneelen FJ (1993). Effects of the peroxisome proliferator mono(2-ethylhexyl)phthalate in primary hepatocyte cultures derived from rat, guinea pig, rabbit and monkey. Relationship between interspecies differences in biotransformation and peroxisome proliferating potencies. Biochem Pharmacol45: 2425—2434.
13.
Dostal LA, Chapin RE, Stefanski SA, Harris MW, Schwetz BA (1988). Testicular toxicity and reduced Sertoli cell numbers in neonatal rats by di(2-ethylhexyl)phthalate and the recovery of fertility as adults. Toxicol Appl Pharmacol95: 104—121.
14.
Elcombe CR, Mitchell AM (1986). Peroxisome proliferation due to di(2-ethylhexyl)phthalate (DEHP): Species differences and possible mechanisms. Environ Health Perspect70: 211—219.
15.
Elcombe CR, Bell DR, Elias E., Hasmall SC, Plant NJ (1996). Peroxisome proliferators: Species differences in response of primary hepatocyte cultures. Ann NY Acad Sci804: 628—635.
16.
Gray TJ, Rowland IR, Foster PMD, Gangolli SD (1982). Species differences in the testicular toxicity of phthalate esters. Toxicol Lett11: 141—147.
17.
Greaves P., Faccini JM (1992). Urinary tract. In: Rat Histopathology. A glossary for use in toxicity and carcinogenicity studies. 2nd edition. Greaves P, Faccini JM (eds). Elsevier Science PublishersNew York, pp 170—188.
18.
Harada T., Maronpot RR, Morris RW, Boorman GA (1990). Effects of mononuclear cell leukemia on altered hepatocellular foci in Fischer 344 rats. Vet Pathol27: 110—116.
19.
Hasmall SC, James NH, Macdonald N., West D., Chevalier S., Cosulich SC, Roberts RA (1999). Suppression of apoptosi s and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalat e (MEHP) and diisononylphthalate (DINP): A comparison of rat and human hepatocytes in vitro. Arch Toxicol73: 451—458.
20.
Jones PS, Savory R., Barratt P., Bell AR, Gray TJB, Jenkins NA, Gilbert DJ, Copeland NG, Bell DR ( 1995). Chromosomal localization, inducibility, tissue-specific expression and strain differences in three murine peroxisome-proliferator-activated-recepto r genes. EurJBiochem233: 219— 226.
21.
Keenan KP, Soper KA, Smith PF, Ballam GC, Clark RL (1995). Diet, overfeeding, and moderate dietary restriction in control Sprague-Dawley rats: I. Effects on spontaneous neoplasms. Toxicol Pathol23: 269—286.
22.
Kliewer SA, Forman BM, Blumberg B., Ong ES, Borgmeyer U., Mangelsdorf DJ, Umesono K., Evans RM (1994). Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci91: 7355—7359.
23.
Kurata Y., Kidachi F., Yokoyama M., Toyota N., Tsuchitani M., Katoh M. (1998). Subchronic toxicity of di(2-ethylhexyl)phthalate in common marmosets: Lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. Toxicol Sci42: 49—56.
Maloney EK, Waxman DJ (1999). trans-Activation of PPARα and PPARγ by structurally diverse environmental chemicals. Toxicol Appl Pharmacol161: 209—218.
26.
Maronpot RR , Harada T., Murthy ASK, Boorman GA (1989). Documenting foci of hepatocellular alteration in two-year carcinogenicity studies: Current practices of the National Toxicology Program. Toxicol Pathol17: 675— 683.
27.
Motojima K. , Peters JM, Gonzalez FJ (1997). PPARα mediates peroxisome proliferator-induced transcriptional repression of nonperoxisoma l gene expression in mouse. Biochem Biophys Res Comm230: 155—158.
28.
National Research Council ( 1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC.
29.
Oishi S. (1985). Reversibility of testicular atrophy induced by di(2-ethylhexyl) phthalate in rats. Environ Res36: 160—169.
30.
Prentice DE , Meikle AW (1995). A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man. Human Exper Toxicol14: 562—572.
31.
Sheldon WG, Bucci TJ, Blackwell B., Turturro A. (1996). Effect of ad libitum feeding and 40% feed restriction on body weight, longevity, and neoplasms in B6C3F1, C57BL6, and B6D2F1 mice. In: Pathobiology of the Aging Mouse , Mohr U, Dungworth DL, Capen CC, Carlton WW, Sundberg JP, Ward JM (eds). ILSI Press, Washington, DC.
32.
Short RD, Robinson EC, Lington AW, Chin AE ( 1987). Metabolic and peroxisome proliferation studies with di(2-ethylhexyl)phthalate in rats and monkeys. Toxicol Ind Health3: 185—195.
33.
Short BG, Goldstein RS (1992). Nonneoplastic lesions in the kidney. In: Pathobiology of the Aging Rat, Mohr U , Dungworth DL, Capen CC (eds). ILSI Press, Washington, DC, pp 211—226.
34.
Sjöberg P., Lindqvist NG, Plö en L. (1986). Age-dependent response of the rat testes to di(2-ethylhexyl) phthalate. Environ Health Perspect65: 237— 242.
35.
Ward PA ( 1975). Inflammation. In: Principles of Pathobiology , 2nd edition, LaVia MF, Hill Jr RB (eds). Oxford University Press, New York, pp 97—140.
36.
Ward JM, Peters JM, Perella CM, Gonzalez FJ (1998). Receptor and non-receptor mediated organ- specific toxicity of di(2-ethylhexyl) phthalate (DEHP) in peroxisome proliferator- activated receptor α-null mice. Toxicol Pathol26: 240—246.
37.
Youssef J., Badr M. ( 1999). Biology of senescent liver peroxisomes: Role in hepatocellular aging and disease. Environ Health Perspect107: 791— 797.
38.
Zerban H., Bannasch P. (1983). Spongiosis hepatis in rats treated with low levels of hepatotropic nitrosamines. Cancer Lett.19: 247—252.
