Evaluating Lead Bioavailability Data by Means of a Physiologically Based Lead Kinetic Model

A method of bioavailability estimation is presented in whicha physiologically based kinetic model of lead kinetics is fitsimultaneously to blood and bone lead concentrations after aperiod of exposure to dietary lead. Optimization of the simultaneousfit, varying only fractional absorption, gives the best estimateof fractional bioavailability for each treatment group. Theanalysis was applied to data from three separate studies inwhich rats were fed for 30 consecutive days purified diets containinglead added as lead acetate, mine waste-contaminated test soils,or mine waste itself. Fractional absorption decreased as leadintake increased, regardless of the source of the lead; butthe magnitude of this dose dependence was lead source-dependent.There were no differences in lead absorption by male and femalerats when lead intake was expressed per unit body weight. Fractionalabsorption varied from 4 to 5%, at low exposure rates (1–2mg lead/kg/day) when lead acetate was added to the diet, to0.24% at a high exposure rate (24 mg/kg/day) when a mine waste-contaminatedtest soil was added to the diet. Comparison of the results ofthis analysis with the results of a more conventional analysis,in which the bone and blood lead concentrations were separatelycompared with bone and blood lead concentrations in rats givendaily injections of lead acetate intravenously for 29 consecutivedays, demonstrated that the standard analysis failed to revealthe dose dependence of fractional absorption.     

Subchronic Effects of Dieldrin and Phenobarbital on Hepatic DNA Synthesis in Mice and Rats

Dieldrin, an organochlorine pesticide, has been shown to behepatocarcinogenic in mice but not rats. Phenobarbital, in contrast,induces hepatic tumors in both mice and rats. Previous studieshave shown that acute dietary exposure of rats or mice to eitherdieldrin or phenobarbital produces several liver changes, includingcentrilobular hypertrophy, induction of hepatic cytochrome P450,and increased liver weight. The present study examined the subchroniceffect of dieldrin (0.1, 1.0, 3.0, 10.0 mg dieldrin/kg diet)and phenobarbital (10, 50, 100, 500 mg phenobarbital/kg diet)on the induction of hepatic DNA synthesis and hepatocyte lethalityin male B6C3F1 mice and male F344 rats. Eight-week-old animalswere treated as above and evaluated for hepatic DNA synthesisafter 7, 14, 21, 28, and 90 days of continual treatment to dieldrinor phenobarbital. Maximal induction of hepatic DNA synthesisin mice was seen at the 14-, 21-, and 28-day sampling times.In rats, no significant increase in hepatic DNA synthesis orhepatocyte lethality was observed at any dose of dieldrin investigated.Phenobarbital produced a significant increase in hepatic DNAsynthesis in both rat and mouse liver following 7 days of treatment.The induction of DNA synthesis in rat liver was transient, withthe labeling index returning to control levels by 14 days oftreatment. In contrast, mice treated with phenobarbital showeda significant increase in hepatic DNA synthesis throughout thetreatment. In both mice and rats, dieldrin and phenobarbitalinduced hepatic DNA synthesis selectively in the centrilobularregion of the hepatic lobule. The lack of an increase in serumenzymes indicative of hepatic damage and the absence of liverhistopathology in mice or rats fed dieldrin or phenobarbitalindicate that the induction of DNA synthesis was not mediatedby a cytolethal, compensatory hyperplastic response, suggestinga mitogenic mechanism. Therefore, the species-specific inductionof hepatic DNA synthesis by either dieldrin or phenobarbitalcorrelated with the previously observed species-specific inductionof hepatic cancer by these two compounds.     

Chronic Dietary Toxicity/Oncogenicity Studies on 2,4-Dichlorophenoxyacetic Acid in Rodents

Forms of 2,4-dichlorophenoxyacetic acid (collectively knownas 2,4-D) are herbicides used to control a wide variety of broadleafand woody plants. Doses in the 2-year chronic/oncogenicity ratstudy were 0, 5, 75, and 150 mg/kg/day. The chronic toxicityparalleled subchronic findings, and a NOEL of 5 mg/kg/day wasestablished. A slight increase in astrocytomas observed (inmales only) at 45 mg/kg/day in a previously conducted chronicrat study was not confirmed in the present study at the highdose of 150 mg/kg/day. Doses in the 2-year mouse oncogenicitystudies were 0, 5, 150, and 300 mg/kg/day for females and 0,5, 62.5, and 125 mg/kg/day for males. No oncogenic effect wasnoted in the study. In summary, the findings of these studiesindicate low chronic toxicity of 2,4-D and the lack of oncogenicresponse to 2,4-D following chronic dietary exposure of 2,4-Din the rat and mouse.     

Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

Retinoids in clinical use today are known to induce hypertriglyceridemiaas one of their major side effects. The purpose of the presentstudy was to determine, in an appropriate animal model, if retinoid-inducedhypertriglyceridemia is mediated by retinoic acid receptors(RARs) and/or by retinoid X receptors (RXRs). Oral gavage ofmale Fischer rats with 13-cis-retinoic acid for 6 days causeda rapid and sustained increase in serum triglycerides that wasreversible within 4 days posttreatment In subsequent experiments,rats were treated by gavage once daily for 3 days with variousretinoids, and serum triglyceride levels were determined 24hr after the last treatment without fasting. All-trans-and 13-cis-retinoicacid, which can be converted to both RAR and RXR agonists, and9-cis-retinoic acid, an RAR/RXR pan-agonist, caused dose-dependentincreases in serum triglycerides at doses that did not causeweight loss or mucocutaneous toxicity. Ro 13–6298 andAGN 190121, two RAR-specific agonists, caused dose-dependentincreases in serum triglycerides, although Ro 13–6298only induced hypertriglyceridemia at weight-suppressive doses.Two RXR-selective agonists, LG100268 and AGN 191701, failedto induce hypertriglyceridemia or weight loss up to the highestdoses tested. A structural isomer of AGN 190121 that does notactivate RARs or RXRs, AGN 190727, did not induce hypertriglyceridemia.Hypertriglyceridemia induced by AGN 190121 was significantlyinhibited by co-treatment with an RAR-selective antagonist,AGN 193109. Taken together, these data provide strong evidencethat retinoid-induced hypertriglyceridemia is mediated, at leastin part, by RARs. These data also suggest that RXR-specificagonists may have reduced potential to induce hypertriglyceridemiarelative to RAR-active retinoids.     

MITOCHONDRIAL MYOPATHIES. A CLINICO-PATHOLOGICAL STUDY OF CASES WITH AND WITHOUT EXTRA-OCULAR MUSCLE INVOLVEMENT

Abstract The clinical and pathological features of 28 patients with mitochondrial myopathy were reviewed. The cases were divided into a group with involvement of the extra-ocular muscles alone or with limb muscle involvement, and a group with a facioscapulohumeral syndrome or generalised weakness without extra-ocular muscle involvement. Cardiac and central nervous system manifestations occurred particularly in the first group which included six patients with multisystemic features and two with the complete Kearns-Sayre syndrome. Diabetes mellitus occurred in the second group only. Quantitative histology on limb muscle biopsies showed a higher proportion of fibres with abnormal mitochondrial aggregates in the second group. No one type of mitochondrial inclusion or other ultrastructural change was specific for either group of cases. The findings illustrate the clinical heterogeneity of cases of mitochondrial myopathy and the lack of specificity of any of the myopathological changes for different subgroups of patients.     

Frequency and isotype distribution of serum antibodies reactive with dietary proteins in adults with chronic urticaria

Forty-eight adult patients with chronic urticaria have been evaluated for scrum antibodies reactive with bovine milk, chicken ovalbumin or wheat gliadin using a solid-phase enzyme-linked immunosorbent assay (ELISA). Of the chronic urticaria sera, 60.4% contained detectable antibodies reactive with one or more of these dietary antigens, compared with 33.9% of sera from 232 healthy adults (P < 0.001). In particular, antibodies reactive with milk (52%; P < 0.001), ovalbumin (39.6%, P < 0.001) and gliadin (20.8%, P > 0.05) were detected at increased frequencies compared with controls (22.8%, 16.8% and 11.6%, respectively). These serum antibodies were predominantly of the IgG isotype, with an IgG subclass restriction mainly to IgG4 for anti-ovalbumin and anti-gliadin antibodies, and to IgG2 and IgG4 for anti-milk antibodies. The increased frequency of IgG antibodies was not significantly associated with either raised total serum IgE or atopic status.