Systematic update to the mammalian relative potency estimate database and development of best estimate toxic equivalency factors for dioxin-like compounds.

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the 'best estimate TEF' (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data.

Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, pesticides, and diabetes in the Anniston Community Health Survey follow-up (ACHS II): single exposure and mixture analysis approaches.

Dioxins and dioxin-like compounds measurements were added to polychlorinated biphenyls (PCBs) and organochlorine pesticides to expand the exposure profile in a follow-up to the Anniston Community Health Survey (ACHS II, 2014) and to study diabetes associations. Participants of ACHS I (2005-2007) still living within the study area were eligible to participate in ACHS II. Diabetes status (type-2) was determined by a doctor's diagnosis, fasting glucose ≥125 mg/dL, or being on any glycemic control medication. Incident diabetes cases were identified in ACHS II among those who did not have diabetes in ACHS I, using the same criteria. Thirty-five ortho-substituted PCBs, 6 pesticides, 7 polychlorinated dibenzo-p-dioxins (PCDD), 10 furans (PCDF), and 3 non-ortho PCBs were measured in 338 ACHS II participants. Dioxin toxic equivalents (TEQs) were calculated for all dioxin-like compounds. Main analyses used logistic regression models to calculate odds ratios (OR) and 95 % confidence intervals (CI). In models adjusted for age, race, sex, BMI, total lipids, family history of diabetes, and taking lipid lowering medication, the highest ORs for diabetes were observed for PCDD TEQ: 3.61 (95 % CI: 1.04, 12.46), dichloro-diphenyl dichloroethylene (p,p'-DDE): 2.07 (95 % CI 1.08, 3.97), and trans-Nonachlor: 2.55 (95 % CI 0.93, 7.02). The OR for sum 35 PCBs was 1.22 (95 % CI: 0.58-2.57). To complement the main analyses, we used BKMR and g-computation models to evaluate 12 mixture components including 4 TEQs, 2 PCB subsets and 6 pesticides; suggestive positive associations for the joint effect of the mixture analyses resulted in ORs of 1.40 (95% CI: -1.13, 3.93) for BKMR and 1.32 (95% CI: -1.12, 3.76) for g-computation. The mixture analyses provide further support to previously observed associations of trans-Nonachlor, p,p'- DDE, PCDD TEQ and some PCB groups with diabetes.

Multicenter Postmarket Analysis of the Neuroform Atlas Stent for Stent-Assisted Coil Embolization of Intracranial Aneurysms.

BACKGROUND AND PURPOSE: The Neuroform Atlas is a new microstent to assist coil embolization of intracranial aneurysms that recently gained FDA approval. We present a postmarket multicenter analysis of the Neuroform Atlas stent. MATERIALS AND METHODS: On the basis of retrospective chart review from 11 academic centers, we analyzed patients treated with the Neuroform Atlas after FDA exemption from January 2018 to June 2019. Clinical and radiologic parameters included patient demographics, aneurysm characteristics, stent parameters, complications, and outcomes at discharge and last follow-up. RESULTS: Overall, 128 aneurysms in 128 patients (median age, 62 years) were treated with 138 stents. Risk factors included smoking (59.4%), multiple aneurysms (27.3%), and family history of aneurysms (16.4%). Most patients were treated electively (93.7%), and 8 (6.3%) underwent treatment within 2 weeks of subarachnoid hemorrhage. Previous aneurysm treatment failure was present in 21% of cases. Wide-neck aneurysms (80.5%), small aneurysm size (<7 mm, 76.6%), and bifurcation aneurysm location (basilar apex, 28.9%; anterior communicating artery, 27.3%; and middle cerebral artery bifurcation, 12.5%) were common. A single stent was used in 92.2% of cases, and a single catheter for both stent placement and coiling was used in 59.4% of cases. Technical complications during stent deployment occurred in 4.7% of cases; symptomatic thromboembolic stroke, in 2.3%; and symptomatic hemorrhage, in 0.8%. Favorable Raymond grades (Raymond-Roy occlusion classification) I and II were achieved in 82.9% at discharge and 89.5% at last follow-up. mRS ≤2 was determined in 96.9% of patients at last follow-up. The immediate Raymond-Roy occlusion classification grade correlated with aneurysm location (P < .0001) and rupture status during treatment (P = .03). CONCLUSIONS: This multicenter analysis provides a real-world safety and efficacy profile for the treatment of intracranial aneurysms with the Neuroform Atlas stent.

Impact of repeated exposure on the toxicokinetics of BDE 47 in mice.

2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is the major polybrominated diphenyl ether (PBDE) found in environmental samples and human tissue despite its small contribution to global production and usage. Currently, three toxicokinetic studies are available investigating single-dose exposures; this is the first study to investigate toxicokinetic parameters following repeated exposure to BDE 47. The disposition and excretion of BDE 47 was monitored in adult female C57BL/6 mice for 5 days following ten consecutive 1.0-mg/kg oral doses and compared with results from our previous study. Results of the present study suggest greater retention of BDE 47 and nonlinear disposition patterns following repeated exposure to this dose in mice. No target tissues of sequestration or potential toxicity were determined; however, some tissues, such as the liver, demonstrated patterns of interest following repeated exposure that were not previously observed in acute toxicokinetic studies. Repeated exposure to BDE 47 results in higher concentrations remaining in adipose tissue, which demonstrates its potential for bioaccumulation. The data also suggest that excretion of BDE 47 may be decreased following repeated exposure. These results, in combination with evidence of its persistence and toxicity, underlie the need to further understand BDE 47 toxicokinetics across species at steady-state conditions.

Inhibition of 2-fluorenamine-induced mutagenesis in Salmonella typhimurium by vitamin A.

Vitamin A alcohol (retinol) completely inhibited the mutagenicity of the carcinogen 2-fluorenamine (2-FA) in Salmonella typhimurium TA98 when the mutagen was activated by liver microsomes from CFN rats. The mutagenicity of 2-FA activated by 9,000Xg rat liver supernatant S9 was inhibited by retinol to a lesser degree. The decline in the number of his+ revertants was not an artifact due to bacterial killing, inasmuch as retinol was not toxic to the bacteria at levels that totally inhibited mutagenesis by 2-FA. Mutagenesis induced by adriamycin, an antibiotic that does not require metabolic activation for mutagenic potential, was unaffected by vitamin A. These results indicate that retinoids inhibit the metabolic activation of some chemical carcinogens to forms that can interact with DNA. Our findings are consistent with the hypothesis that retinoids may exert anticancer activity by inhibiting carcinogen activation, thereby inhibiting tumor induction. In addition to the more widely accepted role of retinoids in modulating the proliferation of epithelially derived neoplasms.

Effect of blood donation on maximal oxygen consumption.

AIM: This study determined the effect of donating one unit of blood on various physiological parameters associated with a VO2(max) test. METHODS: Ten healthy, male subjects (23+/-4 years, 178+/-7.6 cm, 74.4+/-12.3 kg) completed a VO2(max) test 24 h before donating one unit of blood (~500 mL) and 24 h after donating blood. The Bruce protocol was used to determine the subjects' VO2(max). Physiological responses were measured at the end of the VO2(max) test. A repeated measures ANOVA was used to determine if there were significant (P<0.05) differences in the subjects' physiological responses between the VO2(max) before and after blood donation. RESULTS: Significant differences were found in VO2(max) (mean+/-SD, 3.18+/-0.74 vs 2.87+/-0.53 L.min(-1)), cardiac output (Q, 25+/-5 vs 22.5+/-3.3 L.min(-1)), stroke volume (SV, 134+/-37 vs 121+/-22 mL.beat(-1)), delivery of oxygen (DO(2), 5+/-.87 vs 3.97+/-.68 L.min(-1)), and hemoglobin concentration (Hb, 153+/-12 vs 135+/-16 gm.L(-1)). No significant changes were observed for heart rate (HR); arteriovenous oxygen difference (a-vO(2) diff), systolic blood pressure (SBP), and diastolic blood pressure (DBP). CONCLUSIONS: These findings indicate that donating one unit of blood decreased VO2(max) due to the decrease in Q, which resulted from the decrease in SV since HR was unchanged. The lower VO2(max) along with the decrease in DO(2) would be expected to have a negative effect on athletic performance.

Lack of correlation between sensitivity to growth inhibition and receptor number for transforming growth factor beta in human squamous carcinoma cell lines.

Four human squamous carcinoma cell lines, SCC-9, SCC-12F, SCC-15G, and SCC-25, were examined for sensitivity to the growth-inhibitory and differentiation-inducing effects of transforming growth factor beta (TGF-beta). None of the four cell lines was induced to differentiate, as measured by staining for keratin and by competence of cells to form cross-linked envelopes, by concentrations of TGF-beta as high as 1000 pM. TGF-beta did not inhibit DNA synthesis or proliferation of SCC-12F cells in monolayer culture. Monolayer growth and DNA synthesis of SCC-15G and SCC-25 cells were markedly inhibited by 10 pM TGF-beta, with maximal inhibition between 10 and 100 pM. Inhibition of SCC-15G cells was apparent as early as 8 h after addition of TGF-beta, but inhibition of SCC-25 cells was not measurable until 2 days. Growth inhibition of SCC-15G cells was completely reversible, whereas inhibition of SCC-25 cells was irreversible. When growth of cells was measured in a defined medium supplemented with 0.5% fetal bovine serum, TGF-beta inhibited both the monolayer and clonal growth of SCC-15G cells. The monolayer growth, but not the clonal growth, of SCC-25 cells was inhibited. Growth of SCC-9 cells in confluent cultures was slightly inhibited by TGF-beta, while growth in subconfluent cultures was unaffected. All four cell lines, when assayed for binding of 125I-labeled TGF-beta, displayed high-affinity (KD = 2-44 pM) binding sites. These sites were present in very low numbers (less than 2000 sites/cell) in SCC-9, SCC-15G, and SCC-25 cells. SCC-12F cells contained 2000-5500 high-affinity sites/cell. Thus, a lack of sensitivity to growth inhibition by TGF-beta does not necessarily correlate with an inability to bind the growth factor to specific cell surface receptors. The possibility remains that altered sensitivity to TGF-beta may be due to loss of or changes in the relative proportions of the various TGF-beta receptor types. TGF-beta is believed to play a primary role in control of normal cellular growth and differentiation, and the study of cells with defective responses to this growth factor should help to identify some of the critical points within the growth cycle at which malignant cells may escape normal regulatory controls. The differential responses of these four human squamous carcinoma cell lines to TGF-beta should provide a useful model for studying such control mechanisms.

Increased production of mutagenic metabolites of carcinogens by tissues from senescent rodents.

Activation of the procarcinogens benzo(a)pyrene and 2-fluorenamine by liver homogenates (S9) prepared from senescent male CFN rats and C57BL/6J mice resulted in an enhanced production of mutagenic metabolites when compared to young rodents, as indicated by an enhancement of the induced reversion frequency in a Salmonella typhimurium bioassay. Similar results were observed when carcinogen activation was mediated by purified hepatic microsomes, indicating that the age-related differences in carcinogen activation did not result from aging changes in carcinogen metabolism involving non-microsomal mechanisms. The metabolites of many procarcinogens are thought to be the ultimate carcinogens in mammals. Therefore, the present findings are consistent with the hypothesis that some fraction of the markedly increased of neoplasia observed in senescent mammals is a result of age-related alterations in the metabolism of chemical carcinogens.

Role of transforming growth factor beta in the proliferative effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on human squamous carcinoma cells.

The highly toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has recently been shown to stimulate proliferation of two human squamous carcinoma cell lines, SCC-15G and SCC-25, by decreasing the sensitivity of the cells to high density growth arrest. TCDD is known to alter the activity of several endogenous growth-regulatory compounds, and this study was undertaken to investigate the possibility that modulation of transforming growth factor beta (TGF-beta) activity might be involved in the mechanism of growth stimulation by TCDD. TGF-beta inhibited monolayer growth and DNA synthesis of SCC-15G and SCC-25 cells equally well in the presence and the absence of 10 nM TCDD. TCDD alone stimulated proliferation and inhibited differentiation in both cell lines but had no effect on binding of 125I-TGF-beta to or secretion of TGF-beta by SCC-15G cells. Inhibition of growth of SCC-15G cultures by TGF-beta was incomplete, in that cell number continued to increase even in the presence of 100 pM TGF-beta, although at a greatly reduced rate compared to non-TGF-beta-treated controls. These cells, grown in 100 pM TGF-beta alone, reached growth arrest at the same density as non-TGF-beta-treated cultures but failed to reach density-dependent growth arrest when treated with TCDD. Cells treated for 12 h with TCDD exhibited maximal induction of ethoxyresorufin-O-deethylase activity. TGF-beta inhibited this induction in a dose-dependent manner even when added after a 12-h TCDD pretreatment. The inhibition was rapidly reversible after removal of TGF-beta, indicating that it occurred via a mechanism which did not involve inhibition of very early steps in the TCDD response pathway. These results demonstrate that the stimulatory effect of TCDD on keratinocyte proliferation is not mediated through alterations in TGF-beta activity and that TCDD and TGF-beta appear to exert their opposite effects on cellular proliferation by independent mechanisms.

An assessment of dioxin exposure across gestation and lactation using a PBPK model and new data from Seveso.

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4-39years old and in Subcohort B, the 18 women were 3-17years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations.

Toxicokinetics of BDE 47 in female mice: effect of dose, route of exposure, and time.

2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is present in commercial mixtures of polybrominated diphenyl ethers (PBDEs), which are used as flame retardants in a wide variety of consumer products. Despite its small contribution to PBDE global production and usage, BDE 47 is the major congener found in environmental samples and human tissue. No human data are currently available regarding the toxicokinetics of BDE 47 either as an individual congener or in the commercial mixture. Because previous studies have suggested potential toxicokinetic differences between rodent species, this study was conducted in an effort to fully characterize absorption, distribution, and excretion parameters following a single dose with respect to dose, time, and route of exposure in female C57BL/6 mice. Over 80% of the administered dose was absorbed after oral or intratracheal administration, whereas approximately 62% was absorbed when the dose was applied dermally. Disposition was dictated by lipophilicity as adipose and skin were major depot tissues. BDE 47 was rapidly excreted in the urine and feces. Of particular interest was the amount of parent compound found in the urine, which was a major factor in determining an initial whole-body half life of 1.5 days after a single oral exposure. Elimination, both whole-body and from individual tissues, was biphasic. Initial half-lives were 1-3 days, whereas terminal half-lives were much longer, suggesting the potential for bioaccumulation. This toxicokinetic behavior has important implications for extrapolation of toxicological studies to the assessment of health risk in humans.

Inhibition of human and rat CYP1A2 by TCDD and dioxin-like chemicals.

Dioxins have been shown to bind and induce rodent CYP1A2, producing a dose-dependent hepatic sequestration in vivo. The induction of CYP1A2 activity has been used as a noninvasive biomarker for human exposure to dioxins; while there is a consistent relationship between exposure and hepatic CYP1A2 induction in rodents, this relationship has only been observed in some of the highest exposed human populations. This may be explained by inhibition of CYP1A2 activity by dioxins as some rodent studies demonstrate that rodent CYP1A2 activity can in fact be inhibited by dioxins in vitro. CYP1A2 activity was examined using a series of dioxins to inhibit human and rat CYP1A2 activity in species-specific CYP1A2 SUPERSOMES using three common CYP1A2 substrates. Methoxyresorufin was a more efficient substrate than acetanalide or caffeine in this in vitro system. Rat and human CYP1A2 enzymatic activity is inhibited by TCDD, PCDD, TCDF, 4-PeCDF, and PCBs 126, 169, 105, 118, and 156 in a concentration-dependent manner. These data demonstrate that the in vitro metabolism of prototype substrates is similar between the rat and human CYP1A2 SUPERSOME preparations and that dioxins inhibit CYP1A2 activity in both species. Because of the potential for inhibition of CYP1A2 activity by TCDD and other dioxins, studies examining CYP1A2 induction in dioxin-exposed populations using these substrates should be viewed cautiously.

Age-related changes in glucose metabolizing enzymes in spleen, thymus, and pulmonary lavage cells from F344 rats.

Healthy male Fischer 344 rats were sampled at 6, 12, 18, and 24 months of age. There was no gross pathological evidence or deviations in body weight, hematology, or clinical chemistry that were indicative of disease. Mixed populations of thymus, spleen, and pulmonary cells were obtained for enzymatic analyses. Key enzymes from the hexose monophosphate shunt, glycolysis and the tricarboxylic acid cycle were evaluated to determine if there were tissue-specific or pathway-specific changes that occurred during aging. The enzyme responses among the tissues were not consistent during the aging process. Generally the activities of the glucose metabolizing enzymes in thymus and pulmonary lavage cells decreased with age whereas they increased in the spleen cells. Between 18 and 24 months enzymes representative of all three glucose metabolic pathways decreased in pulmonary lavage cells, whereas the decreases in thymic cells were mainly restricted to glycolytic enzymes. By contrast there were two- to ten-fold increases during aging in all of the splenic enzymes measured except malate dehydrogenase. The alterations in tissue enzyme activities probably reflected the changing cellular populations during aging, and in the thymic and pulmonary lavage cellular environment resulted in a loss of energy production by glucose oxidation, compared to the vigorous activity maintained in spleen.

Intestinal absorption of two glucose analogues in rats of different ages.

Intestinal absorption of nutrients and xenobiotics has been suggested to change during aging. Transport processes were examined using nonmetabolizable glucose analogues as markers in an in situ single pass intestinal perfusion procedure. Male Fischer 344 rats of 2, 4, 10, 16, and 27 months of age were used in this study. At least 7 rats were used per age group. Net active and passive transport were estimated using 0.85% NaCl solutions containing [14C]-3-O-methylglucose (3OMG) and [3H]-2-deoxy-D-glucose (2DG) and phenol red as nonabsorbed volume marker. Rats were anesthetized and approximately 30 cm of jejunum was perfused for 30 min. Final glucose analogue concentrations were corrected for volume changes, and compared with initial concentrations. Changes in marker concentrations were normalized to the dry weight of the perfused intestinal segment. Concurrent exposure to both glucose analogues allowed simultaneous monitoring of active and passive components. Under these conditions, there was no significant change in the net transport of 2DG, a compound absorbed by nonspecific processes (range 17-33 mumoles/g/h). In the same animals, the rate of net 3OMG absorption, an actively transported compound, was generally an order of magnitude greater than 2DG. In addition, net 3OMG absorption was significantly (p less than .05) decreased in the 16- and 27-month-old rats (237 and 181 mumoles/g/h) compared with the 2-, 4- and 10-month-old animals (325, 364 and 398 mumoles/g/h, respectively). There appears to be a gradual decrease in net active transport of glucose with age. The mechanism responsible for this age-related change remains to be explained.

Changes in hepatic microsomal membrane fluidity with age.

There are changes in the mixed function oxidase enzymatic activities of rat hepatic microsomal membranes with age. However, the protein components of the mixed function oxidase system do not appear to change with age. The purpose of this study was to detect possible changes in the fluidity of the lipid component of the microsomal membrane with age. Hepatic microsomes were isolated by differential centrifugation from uninduced, male CFN rats aged 3, 12 and 26 mo. The microsomal membrane fluidity was measured using electron paramagnetic resonance after incorporation of a 5-nitroxide stearic acid spin label into the membrane. The order parameter S decreased with age from 0.586 +/- 0.003 (3 mo) to 0.581 +/- 0.002 (12 mo) to 0.569 +/- 0.003 (26 mo) at 30 degrees C. This indicated an increase in membrane fluidity with age. In membranes labeled with the 16-nitroxide stearic acid, a similar increase in membrane fluidity with age was observed. The order parameter of microsomal membranes from 3 and 26 mo rats was measured over the temperature range 10 degrees to 31 degrees C in steps of 0.9 degrees C. A plot of the log of S versus the reciprocal temperature revealed a phase transition at 24 degrees C in membranes from 26 mo rats, but no phase transition was observed in 3 mo old rats in this temperature range. The change in fluidity of the hepatic microsomal membrane with age may account for some of the observed changes in membrane-bound mixed function oxidase activities with age.

Effect of o-benzyl-p-chlorophenol on drug-metabolizing enzymes in rats.

o-Benzyl-p-chlorophenol (BCP) is widely used as a broad spectrum disinfectant. Treatment of male Fischer 344 rats with BCP resulted in an increase in cytochrome P-450 content and an accompanying decrease in aryl hydrocarbon hydroxylase (AHH) activity in both liver and kidney microsomes. Several other drug-metabolizing enzymes were not affected by BCP treatment. However, in kidney, BCP induced NADPH-cytochrome c reductase and uridine diphosphate glucuronyl transferase activities and caused a small increase in total cytochrome P-450 content and glutathione concentration. The cytochrome P-450 isozymes induced by BCP were fractionated by high pressure liquid chromatography (HPLC). The HPLC profile following BCP treatment most closely resembled that seen after phenobarbital. Using an immunoblotting procedure and a radioimmunoassay, it was shown that the increase in cytochrome P-450 content in the liver after BCP treatment was, in part, due to an increase in the phenobarbital-inducible isozymes, P-450b + e. In the kidney, the increase in total cytochrome P-450 content after BCP exposure was not due to an increase in P-450b + e. The decrease in AHH activity appeared to be caused by noncompetitive inhibition of constitutive AHH activity by BCP. BCP also inhibited benzphetamine demethylation, although to a lesser extent. The failure to observe an increase in benzphetamine demethylase activity in vivo, despite the induction of P-450b, was probably due to the concomitant induction and inhibition of drug-metabolizing enzymes by BCP.

Methoxyresorufin: an inappropriate substrate for CYP1A2 in the mouse.

Hepatic microsomes derived from Cypla2(-/-) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As expected, microsomes from untreated 1a2 KO mice did not have immunodetectable CYP1A2 protein; however, methoxyresorufin-O-demethylase (MROD, 25.5+/-6.1 pmol/min/mg protein) and acetanilide-4-hydroxylation (ACOH, 0.64+/-0.04 nmol/min/mg protein) activities were still present. Furthermore, induction of ethoxyresorufin-O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 1a2 KO mice was accompanied by a greater than 70-fold increase in MROD activity. In contrast, ACOH was only induced 2-fold by TCDD. As with 1a2 KO mice, the parental strains exposed to TCDD or 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) showed substantial EROD and MROD induction, whereas ACOH activity was induced to a lesser degree. PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) resulted in low levels of both EROD and MROD induction. Results indicate that both substrates are subject to metabolism by non-CYP1A2 sources, and the apparent contribution of CYP1A1 activity to methoxyresorufin metabolism makes MROD unsuitable for differentiating CYP1A1 and CYP1A2 activities in the mouse.

The role of structure in the disposition of halogenated aromatic xenobiotics.

Halogenated aromatic xenobiotics such as the chlorinated and brominated biphenyls, naphthalenes, dibenzodioxins, and dibenzofurans are widespread environmental contaminants. The number, position, and nature of the halogen atoms as well as the structure of the aromatic rings influence the disposition of these chemicals in living systems. Absorption is governed primarily by the physical properties of lipophilicity and solubility. Distribution through the blood occurs by nonspecific binding to plasma proteins and cellular components. Liver and adipose tissue are the major depots. Metabolism is a prerequisite for excretion. The highly substituted isomers tend to be resistant to metabolism. The route of excretion shifts from urine to feces with increasing size and number of halogen atoms. Although pharmacokinetic modeling has allowed some predictions to be made from one compound to another or across species, more information on metabolism is required in order to improve the ability to predict the disposition in humans of this class of toxic environmental pollutants.

Workshop on perinatal exposure to dioxin-like compounds. V. Immunologic effects.

The immune system comprises a highly integrated network of multiple tissues and cell types with complicated interactions and effects. It is modulated by the endocrine and nervous systems and there is growing realization of its multifunctionality. The session focusing on immunologic effects of dioxin and related compounds following prenatal exposure involved a review of the immunotoxic effects that have been reported for polyhalogenated aromatic hydrocarbons (PHAHs), a discussion of species differences in responses, and development of the immune system, and data from two ongoing epidemiological studies comparing the immune status of children exposed to higher-than-average concentrations of PHAHs both prenatally and lactationally.

A brief survey of butadiene health effects: a role for metabolic differences.

1,3-Butadiene is a major monomer in the rubber and plastics industry and is one of the highest-production industrial chemicals in the United States. Although not highly acutely toxic to rodents, inhalation of concentrations as low as 6.25 ppm causes tumors in mice. Butadiene is oncogenic in rats, but much higher exposure concentrations are required than in mice. Chronic toxicity targets the gonads and hematopoietic system. Butadiene is also a potent mutagen and clastogen. Differences in the absorption, distribution, and elimination of butadiene appear to be relatively minor between rats and mice, although mice do retain more butadiene and its metabolites after exposure to the same concentration and have a higher rate of metabolic elimination. Recent studies have demonstrated that major species differences appear to occur in the rate of detoxication of the primary metabolite, 3-epoxybutene (butadiene monoepoxide [BDMO]). Mice have the greatest rate of production of BDMO as compared to other species, but the rate of removal of BDMO appears to be less than in other species. Mice have low levels of epoxide hydrolase; rats have intermediate levels; monkeys and humans appear to have high levels of this detoxifying enzyme. Thus, while only low levels of butadiene exposure may result in an accumulation of BDMO in the mouse, much higher levels would be required to result in an elevation of circulating BDMO in other species. The level of this reactive metabolite may be correlated with the species differences in butadiene sensitivity.