Induction of porphyria in the rat by chronic versus acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Chronic oral administration of 1 microgram . kg-1 . week-1 of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to female rats for 16 weeks resulted in hepatic porphyria. In contrast, administration of single oral doses as high as 30 micrograms/kg did not produce porphyria, either acutely or 16 weeks later. Activities of hepatic drug-metabolizing enzymes [aryl hydrocarbon hydroxylase (AHH) and glucuronyl transferase] were increased by chronic oral doses of TCDD as low as 0.01 microgram . kg-1 . week-1. When animals were dosed with TCDD chronically and then allowed to recover for 6 months, AHH and glucuronyl transferase activities returned toward normal (98 and 86% recovery). However, animals showed only partial recovery from TCDD-induced porphyria. Hepatic porphyrin levels did decrease during this period, but urinary porphyrins and the rate-limiting enzyme in porphyrin synthesis, delta-aminolevulinic acid synthetase, remained maximally elevated during the 6-month recovery period. It is concluded that single doses of TCDD do not produce porphyria in the rat, but that TCDD is porphyrogenic when given chronically. Moreover, when TCDD administration is stopped, recovery from the porphyrogenic effects of TCDD is very slow and does not correlate with the biological half-life of TCDD in the rat.