1. Baker, T., Kalimi, G., Lington, A., Isenberg, J., Klaunig, J., and Nikiforov, A. (1996). Gap junctional intercellular communication (GJIC) studies on 5 phthalate monoesters in hepatoctyes of four species: Implications for risk assessment. The Toxicologist 30:208
This abstract documented that phthalates did not inhibit GJIC in non-rodent species (i.e., GJIC inhibition, like peroxisomal proliferation is a rodent-specific effect).

2. Barber, E., Astill, B., Moran, E., Schneider, B., Gray, T., Lake, B., and Evans, J. (1987). Peroxisome induction studies on seven phthalate esters. Toxicology and Industrial Health 3:7-22.

This paper documented that high doses of phthalates induced peroxisome proliferation in rodent liver.

3. Caldwell, D., Eldridge, S., Lington, A., and McKee, R. (1999). Retrospective evaluation of alpha 2u-globulin accumulation in male rat kidneys following high doses of diisononyl phthalate. Toxicological Sciences 51:153-160.

This paper documented that DINP produced kidney tumors via an alpha 2ug-mechanism.

4. Isenburg, J., Kamendulis, L., Ackley, D., Smith, Pugh, Jr., J., Lington, A., McKee, R., Kalunig, J. (2001) Reversibility and Persistence of Di - 2-ethylhexyl Phthalate (DEHP) - and Phenobarbital-Induced Hepatocellular Changes in Rodents. Toxicological Sciences 64:192-199.

This paper documents that markers of peroxisomal proliferation, including liver weight increases and enzyme levels, as well as inhibition of gap junctional intercellualr communication continue with phthalate treatment but reverse when treatment is terminated.

5. Isenberg, J., Kamendulis, L., Smith, J., Ackley, D., Pugh, G., Lington, A., and Klaunig, J. (2000). Effects of di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular communication (GJIC), DNA synthesis, and peroxisomal beta oxidation (PBOX) in rat, mouse and hamster liver. Toxicological Sciences 56:73-85.

This paper documented that DEHP inhibited GJIC in rat and mouse.

6. Isenberg, J., Baker, T., Kalimi, G., Lington, A., Klaunig, J., and Nikiforov, A. (1996). Gap junctional intercellular communication (GJIC) studies on mono-2-ethylhexyl phthalate (MEHP) in rat hepatocytes: Effects of modulators on oxidative stress, signal transduction, peroxisomal beta oxidation (PBOX) and P450 pathways. The Toxicologist 30:208.

This paper documented that monohexyl phthalate, the monoester corresponding to DEHP, inhibits gap junction intercellular communication in rat hepatocytes in culture.

7. Kaufmann, W., Deckardt, K., McKee, R., Butala, J., and Bahnemann, R. (2002). Tumor induction in mouse liver - Di-isononyl phthalate (DINP) acts via peroxisomal proliferation. Journal of Regulatory Toxicology and Pharmacology, in press.

This abstract documented that peroxisome proliferation occurs under the conditions of the bioassay in mice.

8. Lake, B., Cook, W., Worrell, N., Cunninghame, M., Evans, J., Price, R., Young, P., and Carpanini, F. (1991). Dose-response relationships for induction of hepatic peroxisome proliferation and testicular atrophy by phthalate esters in the rat. Human and Experimental Toxicology 10:67-68.

This paper documented that phthalates produce peroxisomal proliferation in rat liver and that some but not all cause testicular atrophy when given in high doses to juvenile rats.

9. McKee, R. (2000). The role of inhibition of gap junctional intercellular communication in rodent liver tumor induction by phthalates: Review of data on selected phthalates and the potential relevance to man.
Regulatory Toxicology and Pharmacology 32:51-55.

This paper reviewed the evidence that GJIC inhibition is a rodent-specific process.

10. Roberts, R. (1999). Peroxisome proliferators: Mechanisms of adverse effects in rodents and molecular basis for species differences. Archives of Toxicology 73:413-418.

This paper reviewed the evidence showing that peroxisome proliferation is not relevant for humans.

11. Schoonhoven, R., Bodes, E., and Swenberg, J. (2001). Di(isononyl)phthalate binds reversibly to a2u-globulin and induces cell proliferation in male rat kidneys. The Toxicologist 60:286.

This abstract provided evidence that the kidney tumors are male rat specific and not relevant to humans.

12. Smith, J., Isenberg, J., Pugh, G., Kamendulis, L., Ackley, D., Lington, A., and Klaunig, J. (2000). Comparative in vivo hepatic effects of di-isononyl phthalate (DINP) and related C7-C11 dialkyl phthalates on gap junctional intercellular communication (GJIC), peroxisomal beta oxidation (PBOX) and DNA synthesis in rat and mouse liver. Toxicological Sciences 54:312-321.

This paper documented that phthalates induce peroxisomal proliferation and inhibit GJIC in rodents.

13. Valles, E., Laughter, A., Dunn, C., Cannelle, S., Swanson, C., Cattley, R., and Corton, J. (2003). Role of the peroxisome proliferator-activated receptor alpha in response to diisononyl phthalate. Toxicology 191:211-225.

This paper shows that DINP causes rodent liver tumors via a mechanism of peroxisome proliferation, which is generally believed to be not be relevant to humans.

Sponsored by the Phthalate Esters Panel (in whole or in part).

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