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Biomedical subjects

R J Kavlock

Publications and source records attributed to R J Kavlock.

At least 55 records · Page 3Linked to original sources
PubMed1993

The developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative dose-response modeling for estimation of benchmark doses.

The developmental toxicity of the alternative motor vehicle fuel methanol was assessed in mice by the inhalation route. Pregnant CD-1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm methanol for 7 hr/day on days 6-15 of gestation. Sham-exposed controls were exposed to filtered air under similar conditions. Additional control groups were left in their home cages either unhandled or food-deprived for 7 hr/day to match the food deprivation experienced by the exposed mice. Dams were observed twice daily and weighed on alternate days during the exposure period. Blood methanol concentrations were determined in some mice on gestation days 6, 10, and 15. On day 17, the remaining mice were weighed and killed and the gravid uteri removed. Implantation sites, live and dead fetuses and resorptions were counted, fetuses were examined externally and weighed as a litter. Half of each litter was examined for skeletal morphology and the other half of each litter was examined for internal soft tissue anomalies. One dam died in each of the 7,500, 10,000, and 15,000 ppm methanol exposure groups, but no dose-response relationship was evident for maternal death. The sham-exposed and food-deprived controls as well as all methanol exposed dams gained less weight than did unexposed dams fed ad libitum, but methanol did not exacerbate this effect. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased embryo/fetal death at 7,500 ppm and above (including an increasing incidence of full-litter resorptions), and reduced fetal weight at 10,000 ppm and above. A dose-related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study was 1,000 ppm. A log-logistic dose response model was applied to the incidence data for exencephaly, cleft palate, resorption and cervical rib, and maximum likelihood estimates (MLEs) and benchmark dosages (BDs, the lower 95% confidence interval of the MLEs) corresponding to 1% and 5% added risk above background were calculated. The MLE for 5% added combined risk of having either exencephaly or cleft palate or being resorbed was 3667 ppm, and the corresponding BD was 3,078 ppm. For cervical rib, the 5% added risk values for the MLE and BD were 824 and 305 ppm, respectively. The BDs for 1% added risk were 1915 ppm for exencephaly, cleft palate or resorption, and 58 ppm for cervical rib.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗
PubMed1993

Effects of 5-fluorouracil on embryonic rat palate in vitro: fusion in the absence of proliferation.

5-Fluorouracil (5-FU) inhibits the enzyme thymidylate synthetase (TS) which results in inhibition of DNA synthesis. 5-FU is teratogenic in many species, inducing cleft palate, limb, and tail defects. In the present study, gestation day (GD) 14 embryonic rat craniofacial explants were exposed to 5-FU in organ culture with increasing concentrations and durations of exposure. Palates exposed to 5-FU were morphologically abnormal and craniofacial shape, size, and palatal fusion pattern were affected with the severity of effects dependent on concentration and duration of exposure. Cleft palate was induced in vitro as opposing palates overlapped in a narrowed oral cavity. Palates exposed to higher levels of 5-FU were growth inhibited, but fused even though proliferation ceased and few cells were available to participate in elevation and fusion. This was demonstrated as a biphasic concentration-response profile for palatal fusion in which 0.05 to 0.15 micrograms 5-FU/ml produced decreasing rates of palatal fusion, while exposure to 0.15 to 3.0 micrograms/ml resulted in progressively increasing rates of fusion. The effects of 5-FU were detected biochemically as a reduction in TS activity which was concentration and time dependent during the first 12 hours, with a return to control levels by 24 hours. During the first day, 5-FU did not alter protein levels, but DNA levels significantly decreased at the high concentration, 2.0 micrograms/ml. After 5 days in culture, both DNA and protein decreased with increasing 5-FU concentration and duration of exposure. Also by the end of the culture period, 3H-TdR incorporation had decreased in a concentration dependent manner. It is concluded that progressive inhibition of proliferation and growth in organ culture results in two different morphological outcomes: cleft palate resulting from a narrowed oral cavity and increased incidence of anterior palatal fusion under conditions of strong growth reduction. This study demonstrates that elevation and fusion can occur in the absence of growth and proliferation. Based on these observations, severe inhibition of growth or proliferation would not necessarily be sufficient to induce cleft palate.

Animals↗
PubMed1993

Fetal development in the rat following disruption of maternal renal function during pregnancy.

Pregnant Sprague-Dawley rats received subcutaneous injections of mercuric chloride (1-4 mg/kg) on either gestation day 7, 9, 11, or 13 to determine effects of altered maternal renal function on embryonic and fetal development. Maternal renal function, assessed by urinalysis, was markedly disrupted for at least 48 hours after treatment and resulted in decreased maternal body weight gain. Residual effects on maternal kidney weight were evident on GD 21 when the females were killed and the fetuses removed and examined for visceral and skeletal development. We did not observe an increased incidence of malformations in the offspring for exposure on any day of gestation. Maternal exposure to mercuric chloride slightly impaired fetal growth over several gestational exposures periods and changed the pattern of rib formation when exposure occurred early in organogenesis. The extent of the changes could not, however, be related to the immediate degree or duration of altered maternal renal function. Rather, we found correlations between lasting effects of exposure as measured by maternal renal weight on GD 21 and super-numerary lumbar rib induction on GD 7 and 9; while for the relationship with fetal weight, the strongest correlation with maternal kidney weight occurred following exposure on GD 9 (P < 0.01), with weaker correlations (P < 0.10) for GD 7 and 13 exposures. Maternal serum urea was negatively correlated with fetal weight from the GD 7 exposure. This study supports the concept that some specific forms of maternal toxicity may be associated with limited manifestations of developmental toxicity, but, in general, embryonic development was observed to proceed normally in the presence of marked disruptions in maternal renal physiology. Maternal toxicity, especially as routinely measured in developmental toxicity studies, cannot be looked upon as a single disease. Instead, each manifestation must be examined for what it signifies to the physiology and well being of the female and for cause-and-effect relationships with fetal observations. Maternal toxicity and developmental toxicity should not be etiologically linked solely because of their concurrent appearance on the dose-response curve.

Acute Kidney Injury↗
PubMed1993

Toxicokinetics and structure-activity relationships of nine para-substituted phenols in rat embryos in vitro.

The purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols in rat embryo culture. The uptake of nine radiolabeled para-substituted phenols by day 10 (9-13 somite stage) rat embryos in vitro was determined from 1 to 42 hrs after being placed in culture media containing various phenols. Uptake was rapid, having a half-life of 3 hr or less, with 7 of the nine compounds having uptake half-times of less than one hour. The equilibrium concentration in the embryo ranged from 53 to 136% of the media concentration, indicating only a factor of 2 in maximum discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decreased with increasing log P (octanol/water partition coefficient). The binding was calculated to be 50% for log P = 1.77 from the fitted regression equation and decreased by a factor of 5.9 for every decade increase in P. When hepatocytes were also present in the media the equilibrium concentration in the embryos was less than when hepatocytes were absent. With the limited data, four of the phenols appeared to have no (i.e., zero) equilibrium level when hepatocytes were present. Thus the metabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as given by the effective concentration of the phenol in the embryo to cause somite or tail teratological effects was best predicted by the measured unbound fraction.

Animals↗
PubMed1992

In vitro embryotoxicity of a series of para-substituted phenols: structure, activity, and correlation with in vivo data.

The embryotoxicity of phenol and twelve para-substituted congeners on mid-gestation rat embryos was evaluated in vitro. Through application of correlative procedures and stepwise regression, equations describing the relationship between physical-chemical properties and various measures of activity were developed. Embryotoxicity was quantified by the log of the reciprocal of the potency estimates for reduction in selected growth parameters and induction of four morphological defects. In general, co-cultured hepatocytes ameliorated embryotoxicity; only phenol-induced embryotoxicity was enhanced by the presence of hepatocytes. In the absence of hepatocytes, measures of growth retardation were positively correlated with molar refractivity of the phenols. With hepatocytes, lipophilicity became important for describing the potential to induce growth deficits. The structural defects had varying correlation patterns in both culture systems. Potencies of these congeners in vitro were also compared to maternal and developmental potencies observed in vivo (Kavlock, Teratology, 41:43-59, '90). Two of the congeners were very toxic in both systems. For the remaining congeners, one maternal toxicity measure was found to be positively correlated with embryotoxicity for growth and development in vitro without hepatocytes. With hepatocytes, a broad spectrum of correlations, both positive and negative, were observed between in vivo developmental toxicity endpoints and in vitro embryotoxicity. Data from preliminary dosimetry studies suggest that phenol congeners may accumulate in embryos exposed in vitro more readily than with in vivo exposure. Potency calculations based on dosimetry information may demonstrate better correlations between data and allow additional relationships between chemical structure and activity to be developed.

Animals↗
PubMed1992

Thyroid hormone differentially regulates cellular development in neonatal rat heart and kidney.

The role of thyroid hormone in the control of cardiac and renal cell development was examined in neonatal rats made hyperthyroid by administration of triiodothyronine (T3, 0.1 mg/kg s.c. on postnatal days 1-5) or hypothyroid by administration of propylthiouracil (PTU, 20 mg/kg s.c. given to dams on gestational day 17 through postnatal day 5 and to pups on postnatal days 1-5). Indices of total cell number (total DNA per tissue), cell packing density (DNA per g tissue), and relative cell size (protein/DNA ratio) were evaluated from birth through young adulthood. PTU administration led to primary shortfalls in cell number that were of similar magnitude in both tissues, but persisted somewhat longer in the kidney than in the heart. Deficits in cell packing density and cell size in the hypothyroid animals were secondary to the effect on cell number, displaying smaller magnitudes of effect and a lag in appearance and disappearance of the deficits compared to that for total DNA; indeed, the phase in which tissues were restoring their cell numbers was accompanied by increased cell packing density, reflecting a more rapid restitution of cell numbers than tissue weight or cell size. In contrast to the relatively similar effects of PTU on developing cardiac and renal cells, the effects of T3 were selective for the heart. Although T3 caused general growth impairment, it evoked marked cardiac overgrowth that was accompanied by a striking increase in cell number and a small increase in cell size. The cardiac hyperplasia is unique to the developing animal, as post-replicative heart cells in adult animals show only hypertrophy in response to thyroid hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Gonadal effects of fetal exposure to the azo dye congo red in mice: infertility in female but not male offspring.

The present study describes the relationship between gonadal agenesis and fertility in male and female mice exposed in utero to the diazo dye Congo red (CR). Maternal CR treatment inhibited testicular and ovarian function in the offspring after oral administration of 1 or 0.5 g/kg/day on Gestational Days 8-12. The testes of male offspring from CR-exposed dams were small in size and contained hypospermatogenic seminiferous tubules. However, despite the fact that testis weight was reduced by more than 70% in some males, they displayed normal levels of fertility when mated to untreated females for over 10 months. In contrast, female offspring from CR-exposed dams produced only about half as many litters and pups as the control pairs did under long-term mating conditions. Histological examination of the ovaries revealed that subfertility was correlated with ovarian atrophy. Females lacking maturing follicles were considerably less productive (1.3 litters and 11.5 pups) than treated females with histologically normal ovaries (7.1 litters and 78.1 pups). In summary, prenatal exposure to the dye CR affects the gonads of both male and female offspring, but only the female offspring display reduced fertility.

Animals↗
PubMed1992

Fetal dexamethasone exposure accelerates development of renal function: relationship to dose, cell differentiation and growth inhibition.

Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. Nevertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. The current study examined this apparent paradox in the developing rat kidney, using doses of dexamethasone that span the threshold for growth impairment: 0.05 or 0.2 mg/kg given on gestational days 17, 18 and 19. At the lower dose, which did not significantly retard body growth, the postnatal development of tubular reabsorptive capabilities for sodium, potassium, osmotic particles, water and urea was accelerated. These effects were less notable at the higher dose, which caused initial body growth impairment. The selectivity toward promotion of tubular function was evidenced by the absence of effect of either dose of dexamethasone on development of glomerular filtration rate. Because of the wide spectrum of dexamethasone's effects on tubular function, we also assessed fetal kidney adenylate cyclase as a means of detecting altered cell differentiation in the prenatal period during which dexamethasone was given. Either glucocorticoid dose increased the total adenylate cyclase catalytic activity (assessed with forskolin). Thus, the net effect of fetal dexamethasone exposure on development of renal excretory capabilities probably represents the summation of promoted cell differentiation and slowed development consequent to growth retardation. At low dose levels, the former effect predominates, leading to enhanced functional development, whereas higher doses that interfere with general growth and development can offset the direct promotional effect.

Adenylyl Cyclases↗
PubMed1991

Physiological consequences of early neonatal growth retardation: effects of alpha-difluoromethylornithine on renal growth and function in the rat.

The physiological consequences of early neonatal growth retardation in the kidney were investigated using alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines. We administered by s.c. 500 mg/kg/day DFMO, or saline, to Sprague-Dawley rat pups from the day of birth through postnatal day (PD) 6 and evaluated renal function on PD 4, 7, 10, and 13 using tests of basal renal clearance and urinary concentrating ability. Kidney weights and gross pathology were also obtained. On PD 39, serum chemistries and organ weights were determined. In a second experiment, we evaluated concentrating ability on PD 7-10, and basal renal function, concentrating ability, diuretic response, serum chemistries, and organ weights on PD 132-140. DFMO selectively inhibited renal growth but did not inhibit glomerular and tubular functional maturation. In fact, the rates of filtration and reabsorption (per g renal tissue), and concentrating ability were increased in treated pups. These changes were associated with long-term effects on renal function, including uremia, glucosuria, and male-specific concentrating deficits in adulthood. Several hypotheses can be developed concerning the physiological mechanisms underlying these changes (e.g., altered renal urea metabolism), which in turn may reflect either a direct role of ODC in the regulation of maturation or secondary consequences of inhibition of ODC.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Activity profiles of developmental toxicity: design considerations and pilot implementation.

The available literature was searched for quantitative test results from both in vitro and in vivo assays for developmental toxicity for five model compounds: cyclophosphamide, methotrexate, hydroxyurea, caffeine, and ethylenethiourea. These compounds were chosen on the basis of their extensive utilization in a variety of assay systems for developmental toxicity as evidenced by their representation in the ETIC database (each generally has 100-500 citations encompassing multiple test systems). Nine cellular-based assays, six assays using whole embryos in culture, as well as Segment II and abbreviated exposure tests for mammalian test species are included in the database. For each assay, the critical endpoints were identified, each of which was then provided a three-letter code, and the criteria for extraction of quantitative information were established. The extracted information was placed into a computerized reference file and subsequently plotted such that the qualitative (positive/negative) and quantitative (e.g., IC50, highest ineffective dose (HID), lowest effective dose (LED] results across all test systems could be displayed. The information contained in these profiles can be used to compare qualitative and quantitative results across multiple assay systems, to identify data gaps in the literature, to evaluate the concordance of the assays, to calculate relative potencies, and to examine structure-activity relationships.

Animals↗
PubMed1991

Fetal dexamethasone exposure impairs cellular development in neonatal rat heart and kidney: effects on DNA and protein in whole tissues.

Fetal glucocorticoid exposure causes postnatal growth retardation. To examine the mechanisms underlying effects on specific organ systems, we administered 0.2 or 0.8 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19 and assessed three biochemical markers of cell development in heart and kidney of the offspring: DNA content per organ as an index of total cell numbers, DNA per g tissue as an index of cell packing density, and protein/DNA ratio as an index of relative cell size. In both tissues, DNA content became markedly subnormal during the first postnatal week, the ontogenetic period of rapid cell division. Partial recovery occurred by the end of the first postnatal month. In the heart, cell packing density was subnormal initially and the cells were significantly enlarged. In contrast, packing density was slightly elevated in the kidney; protein/DNA was increased by the low dose of dexamethasone, but markedly decreased by the high dose. These results suggest that tissue growth impairment caused by prenatal dexamethasone treatment reflects primary deficits in cell proliferation that extend to a variety of different cell types; however, consequent effects on cell packing density and cell size are dose-specific, possibly reflecting actions of glucocorticoids selective for certain cell types or phases of cell development.

Animals↗
PubMed1991

Prenatal terbutaline treatment: tissue-selective dissociation of perinatal changes in beta-adrenergic receptor binding from regulation of adenylate cyclase activity.

The role of prenatal beta-receptor stimulation in development of adrenergic reactivity was examined by administering the beta-agonist, terbutaline, to pregnant rats on gestational days 17, 18 and 19. On gestational day 20, liver membrane beta-receptor binding capabilities showed the depression characteristic of down-regulation, but heart and kidney receptor binding were essentially normal. Basal adenylate cyclase activity in the fetal liver membrane preparation was unchanged by terbutaline exposure and enzymatic reactivity to beta-adrenergic stimulation showed only a slight lowering; forskolin stimulation, however, was markedly increased in the terbutaline group. By postnatal day 2, receptor binding had returned to normal in the liver and remained at control levels in the other two tissues. Responsivity of adenylate cyclase to beta-receptor stimulation was markedly elevated in heart and kidney membranes; the effect represented an alteration at the level of the cyclase itself, rather than the receptor, since both basal activity and forskolin stimulation of the enzyme showed equivalent enhancement. These data thus suggest that early beta-adrenergic stimulation promotes cellular reactivity by fostering the development of membrane transduction mechanisms, rather than through effects on the receptor ligand binding site per se.

Adenylyl Cyclases↗
PubMed1991

In vivo and in vitro structure-dosimetry-activity relationships of substituted phenols in developmental toxicity assays.

Structure-dosimetry-activity relationships (SDARs) of a series of substituted phenols were evaluated following exposure of gestation day 11 rats in vivo and in comparable stage embryos in vitro. In the in vivo study, 27 congeners were assayed and log P (a term used synomously with lipophilicity in this paper) and Hammett sigma values (a measure of the electronic withdrawing ability of the substituent) were shown to correlate with maternal toxicity; however, no relationships between these parameters and developmental effects were observed. In the in vitro system, 13 congeners were evaluated and molar refractivity and/or lipophilicity were shown to correlate with the ability of the phenols to induce embryonic growth retardation and structural defects in the absence of the hepatocytes. In contrast, when a metabolic activating system (primary hepatocytes) was present in the in vitro system, the potential to induce growth retardation was inversely related to lipophilicity, although the relationships were weaker than the positive relationship seen without the hepatocytes. The binding of the phenols to macromolecules in the culture medium was highly correlated with log P. Correcting the in vitro potency data for the variable amount of binding improved the predictiveness of the quantitative structure-activity relationships (QSARs). The potential to induce embryotoxicity in vitro was not well correlated with the potential to induce developmental toxicity in vivo: whereas the in vitro data demonstrates that the phenols are intrinsically embryotoxic, few of them actually produced significant developmental toxicity in the in vivo system, and there were few positive correlations between effects observed in the two systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1991

Effects on the fetal rat eye of maternal benomyl exposure and protein malnutrition.

Benomyl, a benzimidazole fungicide, produced ocular and craniocerebral malformations in fetal rats when administered to the dams by gavage in a dose of 62.4 mg/kg of maternal body weight/day on days 7-21 of gestation. Ocular anomalies included retinal dysplasia, cataracts, microphthalmia, and anophthalmia. These anomalies occurred in 43.3% of fetuses exposed to benomyl and a normal protein diet but increased to 62.5% when benomyl administration was combined with a protein deficient (8% casein) diet. Microscopic examination of the malformed eyes revealed that the most common abnormality, retinal dysplasia, consisted of rosettes of retinal cells and retinal infolding. The majority of rosettes had a single layer and a limiting membrane. Rosettes with two or three layers were also observed, particularly in fetuses exposed both to protein deficiency and benomyl. Although anophthalmia was identified macroscopically in five fetuses, only a single instance of true anophthalmia was found microscopically. These data support the results of previous investigators that benomyl induces ocular malformation and that protein deficiency enhances the teratogenic effects of benomyl. The disorderly proliferation of retinal cells and rosette formation resembled the periventricular cell masses that accumulate in brains exposed to benomyl and certain other teratogenic agents. The anti-tubulin action of benomyl is known to impair microtubule formation and it may produce brain and ocular malformations by disruption of neuronal proliferation and migration.

Abnormalities, Drug-Induced↗
PubMed1991

Neural factors in the development of renal function: effect of neonatal central catecholaminergic lesions with 6-hydroxydopamine.

Peripheral sympathetic neurons are thought to provide trophic regulatory signals for development of their target tissues. In the current study, we investigated the role of sympathetic tone in the functional development of the kidney in rats, using neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA). This treatment destroys central catecholaminergic pathways and permanently reduces sympathetic activity without ablating peripheral nerve terminals. Renal function was evaluated over the first two postnatal weeks, when glomerular and tubular function undergo rapid development. Although basal renal clearance and the homeostatic response to fluid deprivation developed normally in the lesioned rats, the response to a maximally-effective dose of desmopressin acetate (DDAVP), a vasopressin analog, became deficient by the end of the second week. After weaning, the lesioned animals were unable to survive a chronic salt load, which requires sustained water reabsorption but high output of sodium. These data indicate that normal sympathetic tone is required for appropriate development of the responsiveness of the renal tubule to vasopressin.

Animals↗
PubMed1990

Structure-activity relationships in the developmental toxicity of substituted phenols: in vivo effects.

Hansch analysis, a quantitative approach relating the physical-chemical properties of molecules to biological effects, was applied to a series of substituted phenols tested for developmental toxicity. The physical-chemical properties included a hydrophobic parameter (log P), an electronic parameter (Hammett sigma), and a bulk parameter (molar refractivity (MR]. Biological activities (potencies) were obtained for 27 congeners in a Chernoff/Kavlock Assay performed in Sprague-Dawley rats exposed on day 11 of gestation. The potencies discussed in this report are the following: the dose to decrease maternal weight gain by 10 g at 24 and 72 hours after treatment (MTOX1 and MTOX2); the dose to increase postimplantation loss by 1 over the concurrent control value (PLOSS); and the dose required to decrease total litter weight by 10% on postnatal day 6 (BIO6). A quantitative structure-activity relationship QSAR was developed for the maternal data (1/MTOX1 = (0.0344*log P) + (-0.1503*sigma) + 0.1195; n = 22, r = 0.81, P less than .0001), which related increasing lipophilicity and decreasing electron-withdrawing ability of the substituent on 22 para-phenols to increasing toxicity. Another QSAR was developed from eight para-phenols that had the greatest postimplantation loss potencies (i.e., less than 100 mmol/kg). The model (1/PLOSS = (-0.2676*log P) + (-0.1827*sigma) + (0.0265*MR) + 0.4420; n = 8, r = 0.93, P less than .0298) related decreasing lipophilicity and electron-withdrawing ability and increasing bulk properties to the decreased viability of implantation sites. However, no descriptor was identified that distinguished the more potent from the less potent congeners for postimplantation loss, and no QSAR was found for litter weight on postnatal day 6 (even when limiting the analysis to the more potent congeners). Congeners were also grouped on a qualitative level according to whether they induced a biological effect below a dose of 6 mmol/kg (termed active), between 6 and 11 mmol/kg (moderately active), or greater than 11 mmol/kg (inactive). Overall, 14 of 27 congeners were classified as active in terms of maternal effects, but only 50% of these were active for developmental effects. Seven of the nine overall active developmental toxicants were active maternal toxicants. Four of the developmental toxicants produced a syndrome of effects that may be related to a similar mechanism of action or common metabolic pathway. Thus, from both quantitative and qualitative viewpoints, the properties of these phenolic congeners that promote maternal toxicity are different from those that contribute to developmental toxicity. It is therefore likely that the mechanisms of toxicity behind these effects are also different.

Animals↗