Liver cell hypertrophy

Rats exposed 5 days/week for 13 weeks to concentrations as high as 7060 ppm showed minimal effects to the nervous system as determined by functional observational battery, automated motor activity, and neuropathology. Rats exposed 6 hours/day for 90 days at 7100 ppm had increased liver and kidney weights males also had liver cell hypertrophy and increased hyaline droplets in the proximal tubules. ... 

Two-year studies of rats administered up to 2 500 ppm and mice administered up to 1000 ppm in the diet was associated with Kupffer cell hypertrophy, cytoplasmic vacuolization, and mixed cell foci in the liver of rats but no significant pathologic findings in mice. There was no evidence of carcinogenic activity in either species. 

Other Species. The discussion of hepatic effects in the above subsections is based on effects in rats and mice. Not all animal species are equally susceptible to the hepatic effects of DEHP. Differences in responsiveness are particularly evident with respect to the increases in peroxisomal content of liver cells, induction of peroxisomal enzymes, and increased liver weight (hypertrophy and hyperplasia). Although these responses clearly occur in rats and mice, hamsters are only partially responsive and guinea pigs, and monkeys are refractory. 

The decrease of T4 concentration with the increased thyroid weight and enhanced thyroid follicular cell hypertrophy [28, 29] was induced by an increased activity of a liver enzyme (UDPG-transferase) involved in peroxisome proliferation [33, 35, 36]. This mechanism is also specific to rodents. Therefore, thyroidal effects that were observed in the studies in rats and mice are considered unlikely to be relevant to human health. 

Refractory species such as guinea pig seem to have fewer PPARa receptors in the liver, and observations suggest there are significant differences between rodents and humans in a number of aspects of the response. Recent studies in cynomologous monkeys treated with ciprofibrate have detected peroxisomal proliferation but only found slight changes in certain parameters [e.g., messenger RNA (mRNA) induction for acyl CoA oxidase] of minimal oxidative stress, and despite hypertrophy, cell proliferation was not detected. 

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