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Bruce K Beyer, Neil Chernoff,
Bengt R Danielsson,
Karen Davis-Bruno,
Wafa Harrouk,
Ronald D Hood,
Gemma Janer,
Ulla Wändel Liminga,
James H Kim,
Meredith Rocca,
John Rogers,
Anthony R Scialli
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ABSTRACT: Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36-51, 2010. © 2011 Wiley-Liss, Inc.
Birth Defects Research Part B Developmental and Reproductive Toxicology 02/2011; 92(1):36-51. · 1.93 Impact Factor
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ABSTRACT: The elucidation of mechanisms and pathogenesis of birth defects is exceedingly complex. Consequently, there are few examples where the etiology of birth defects caused by a specific agent has been well described. One such example is the "Edema Syndrome" first described by Casimer Grabowski in the 1960s as a mechanism of hypoxia-induced malformations in the chick embryo. The Edema Syndrome comprised a series of events in the embryo starting with osmotic imbalances followed by edema, distention, blisters, hematomas, and hemorrhage in or near developing structures. Malformation or deformation of structures resulted from mechanical disruption or loss of blood supply. A similar etiology has since been described by others in a variety of laboratory mammals following treatment with drugs including epinephrine, hydroxyurea, cocaine, phenytoin, and potassium channel-blocking drugs. Free radical excess following transient hypoxia may be a common factor in all of these insults. Vascular disruption is also associated with a number of birth defects in humans, including limb and digit reduction defects and urogenital defects.
Birth Defects Research Part B Developmental and Reproductive Toxicology 08/2010; 89(4):300-3. · 1.93 Impact Factor
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Elizabeth D Hilborn,
John W Fournie,
Sandra MFO Azevedo, Neil Chernoff,
Ian R Falconer,
Michelle J Hooth,
Karl Jensen,
Robert MacPhail,
Ian Stewart,
Ellen Rogers,
Glen R Shaw
03/2008: pages 579-606;
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Sandra M F O Azevedo, Neil Chernoff,
Ian R Falconer,
Michael Gage,
Elizabeth D Hilborn,
Michelle J Hooth,
Karl Jensen,
Robert MacPhail,
Ellen Rogers,
Glen R Shaw,
Ian Stewart,
John W Fournie
Advances in experimental medicine and biology 02/2008; 619:579-606. · 1.09 Impact Factor
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ABSTRACT: The axial skeleton is routinely examined in standard developmental toxicity bioassays and has proven to be sensitive to a wide variety of chemical agents. Dysmorphogenesis in the skull, vertebral column and ribs has been described in both human populations and in laboratory animals used to assess potential adverse developmental effects. This article emphasizes vertebrae and rib anomalies both spontaneous and agent induced. Topics discussed include the morphology of the more common effects; incidences in both human and experimental animal populations; the types of anomalies induced in the axial skeleton by methanol, boric acid, valproic acid and others; the postnatal persistence of common skeletal anomalies; and the genetic control of the development of the axial skeleton. Tables of the spontaneous incidence of axial anomalies in both humans and animals are provided.
Birth Defects Research Part B Developmental and Reproductive Toxicology 01/2008; 80(6):451-72. · 1.93 Impact Factor
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ABSTRACT: The haloacetic acids (HAAs) are a family of xenobiotics found in tap water as a result of drinking water disinfection. Administration of HAAs to rats produces a variety of adverse effects, including developmental toxicity. The dysmorphogenic potencies of all nine bromo/chloro-acetic acids have been determined in rodent whole embryo culture using standard 26-h exposure. Since the half-lives of the HAAs in vivo are typically <8 h, the developmental effects of short-term exposures to dihaloacetates were evaluated. Gestation day 8 (3-6 somite pairs) CD-1 mouse conceptuses were exposed to 11,000 microM dichloroacetic acid (DCA), 300 microM dibromoacetic acid (DBA) or 300 microM bromochloroacetic acid (BCA) for culture periods of 1, 3, 6 or 26 h. Following 1, 3 or 6 h of exposure to HAAs, conceptuses were transferred to control medium to complete a 26-h culture period. The amounts of HAAs present in embryos after 1, 3 and 6h of exposure were determined. Increased incidences of dysmorphic embryos were produced by 6 or 26-h exposures to DCA; a 26-h exposure to DBA; or 3, 6 or 26-h exposures to BCA. The dysmorphology produced was dependent upon the length of exposure and chemical. The embryonic concentration of each HAA (104.5, 2.5 and 2.6 pmol/microg protein for DCA, DBA and BCA, respectively) was reached by 1h of exposure and did not change at the subsequent time points examined. The current studies demonstrate that BCA is more potent than DBA or DCA at disrupting embryogenesis since shorter exposures alter morphogenesis. Since the embryonic HAA concentrations were the same at the three time points measured, the time-dependence in dysmorphogenesis does not appear to be a simple function of increasing embryonic concentration of these chemicals. These studies demonstrate that for these dihaloacetic acids relatively high concentrations and long exposures are needed to alter rodent development in vitro.
Reproductive Toxicology 10/2006; 22(3):443-8. · 3.23 Impact Factor
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ABSTRACT: The haloacetic acids (HAA) are a family of chemicals that are drinking water disinfection by-products. We previously reported that haloacetic acids, including several bromo- and chloro-HAAs, alter embryonic development when mouse conceptuses are directly exposed to these xenobiotics in whole embryo culture. Craniofacial dysmorphogenesis was observed in exposed embryos and a quantitative structure activity relationship (QSAR) for induction of cranial neural tube dysmorphogenesis was established for a series of 10 HAAs, which also included fluoro- and iodo-HAA representatives. In the current study, we evaluate the effects of exposing neurulation staged (3-6 somite pairs) CD-1 mouse conceptuses to bromochloro- (BCA), dibromochloro- (DBCA) and bromodichloro-acetic (BDCA) acids in whole embryo culture at concentrations ranging from 50 to 2500 microM. Morphological development was assessed after a 26 h exposure period. Exposure of conceptuses to these HAAs produced dysmorphogenesis, including prosencephalic and pharyngeal arch hypoplasia as well as eye and heart tube abnormalities. Benchmark concentrations for induction of neural tube dysmorphogenesis were 63, 500 and 536 microM for BCA, DBCA and BDCA, respectively. Our previously developed HAA QSAR accurately predicted placement of these three chemicals in the larger context of the previously tested di- and tri-HAAs, also correctly predicting that BCA would be more potent than DBCA and BDCA, and that the latter two HAAs would be near equi-potent. This study describes the concentration-dependent induction of dysmorphogenesis in whole embryo culture by three mixed chloro/bromo-HAAs and demonstrates the ability of the HAA QSAR to predict relative potencies within this family of xenobiotics.
Reproductive Toxicology 05/2006; 21(3):260-6. · 3.23 Impact Factor
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ABSTRACT: Biologically rational regulatory policies with regards to developmental toxicity are often based on the extrapolation of standard laboratory rodent bioassay results to the human population. Significantly contributing to the difficulty of this task is the possibility that general toxic effects on the maternal organism may affect the developing conceptus. This review examines maternal factors which may bear directly or indirectly upon developmental outcome, with emphasis on those of greatest relevance to the hazard assessment process. Standard teratology testing protocols call for top dosage levels that induce overt maternal toxicity, and the developmental effects of this toxicity (both alone, and with concurrent embryo/fetal insult) continue to present regulators with considerable interpretive difficulties. In response to these problems, there have been both research and literature review efforts dealing with the relationship of maternal and developmental toxicity. Maternally mediated developmental toxicity occurs with a number of agents, and toxicant-induced alterations in maternal physiology may affect the conceptus at dosages not causing overt maternal toxicity. Relevant studies are reviewed here, and suggestions for avenues of future research are offered including the identification of any syndromes of developmental effects occurring at maternally toxic levels irrespective of the causative agent, and experimental approaches for the characterization of maternal toxicity.
Toxicology and Applied Pharmacology 10/2005; 207(2 Suppl):367-74. · 4.45 Impact Factor
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ABSTRACT: Supernumerary ribs (SNR) of differing sizes are commonly observed in rodent developmental toxicity studies, and the significance of treatment-related increases in SNR in standard studies has been contentious. We induced dose-related increases in SNR in fetal CD-1 mice by treating on gestation days 7-8 with benomyl (BEN; 0, 75, 150 mg/kg/d), dinoseb (DIN; 0, 30, 50 mg/kg/d); 2-methoxyethanol (2-ME; 0, 75, 150 mg/kg/d), or valproic acid (VPA; 0, 125, 250 mg/kg/d). Incidences of SNR were 9.3-27.6% in controls and 19.3-84.4% in the high dosage groups. SNR length showed a bimodal distribution with peaks at 0.3-0.4 mm and 0.9-1.1 mm in both treated and control groups. Based on length distributions, we used an actual length of 0.6 mm to separate short (rudimentary) from long (extra) SNR. DIN, 2-ME, and VPA induced a dose-related increase of extra ribs, while the incidence of rudimentary ribs remained at control levels. There was no apparent correlation of the presence of either type of SNR in a fetus and the occurrence of other anomalies. These data support the idea that extra and rudimentary SNR may reflect separate developmental phenomena, and should be considered and reported separately in developmental toxicity studies for risk assessment.
Birth Defects Research Part B Developmental and Reproductive Toxicology 03/2004; 71(1):17-25. · 1.93 Impact Factor
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ABSTRACT: 5-Aza-2'-deoxycytidine (dAZA), causes hindlimb phocomelia in CD-1 mice. Studies in our laboratory have examined the hypothesis that compound- induced changes in gene expression may uniquely affect hindlimb pattern formation. The present study tests the hypothesis that dAZA causes limb dysplasia by inducing cytotoxicity among rapidly proliferating cells in the limb bud mesenchyme.
Pregnant CD-1 mice were given a teratogenic dose of dAZA (i.p.) at different times on GD 10 and fetuses evaluated for skeletal development in both sets of limbs by standard methods. Using general histology and BrdU immunohistochemistry, limb mesenchymal cell death and cell proliferation were then assessed in embryos at various times post dosing, shortly after initial limb bud outgrowth. The effect of dAZA on early limb chondrogenesis was also studied using Northern analysis of scleraxis and Alcian blue staining of whole mount limb buds.
Compound related hindlimb defects were not restricted to a specific set of skeletal elements but consisted of a range of temporally related limb anomalies. Modest defects of the radius were observed as well. These results are consistent with a general insult to the limb mesenchyme. Mesenchymal cell death and reduced cell proliferation were also observed in both sets of limbs. The timing and location of these effects indicate a role for cytotoxicity in the etiology of dAZA induced limb defects. These effects also agree with the greater teratogenicity of dAZA in the hindlimb because they were more pronounced in that limb. The expression of scleraxis, a marker of early chondrogenesis, was reduced 12 hr after dAZA exposure, a time coincident with maximal cell death, as was the subsequent emergence of Alcian blue stained long bone anlagen.
These findings support the hypothesis that cytotoxic changes in the limb bud mesenchyme during early limb outgrowth can induce the proximal limb truncations characteristic of phocomelia after dAZA administration.
Teratology 05/2002; 65(4):180-90.
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ABSTRACT: The potential of electric and magnetic fields to adversely affect the health of the human population is an issue which continues to receive a great deal of attention in both public and scientific forums. One of the critical issues is the possibility that such fields may adversely affect the reproductive process. Numerous studies investigating the potential of electric and/or magnetic fields to alter reproduction in vertebrates have been conducted. These studies have, in many instances, yielded seemingly contradictory results. A number of epidemiological studies have been conducted as well. This review of the literature examines relevant studies and attempts to draw biologically rational conclusions from them. The studies are ordered in broad categories based upon both classification of the species studied (i.e. submammalian, mammalian exclusive of man and human) and the agent used (i.e. extremely low frequency electric, very low frequency electric, and magnetic fields). From our review we conclude that laboratory experimental and epidemiological results to date have not yielded conclusive data to support the contention that such fields induce adverse reproductive effects under the test or environmental conditions studied. Additional studies may, however, be warranted to clarify some of the experimental results obtained.
Toxicology 10/1992; · 3.68 Impact Factor
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ABSTRACT: The objective of testing xenobiotics for potential developmental toxicity is to extrapolate laboratory animal information to the human species, thereby deriving biologically rational regulatory policies. One of the problems that significantly contributes to the difficulty of this task is the possibility that general effects on the maternal organism could affect the developing conceptus. Published data have indicated that factors intrinsic to the maternal organism affect developmental outcome. This overview examines factors which may bear directly or indirectly upon developmental outcome, with emphasis on those of greatest relevance to the hazard assessment process. Standard teratology testing protocols often call for dose levels that induce overt maternal toxicity, and the developmental effects of this toxicity (both alone, and with concurrent embryo/fetal insult) continue to present regulators with considerable interpretive difficulties. In response to these problems there have been both research and literature review efforts dealing with the relationship of maternal and developmental toxicity. Relevant studies are reviewed here, and suggestions for avenues of future research are offered including the identification of any syndromes of developmental effects occurring at maternally toxic levels irrespective of the causative agent, and experimental approaches for the characterization of maternal toxicity.
Toxicology 01/1990; · 3.68 Impact Factor
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ABSTRACT: The in vivo teratology screening procedure described previously [Chernoff N, Kavlock RJ: J Toxical Environ Health 10:541–550, 1982] was further evaluated using a total of 46 chemicals in 50 different treatment regimens. Pregnant CD-1 mice were generally treated by oral gavage on days 8–12 of gestation at a dose level predicted from a preliminary range finding study to induce a slight degree of maternal toxicity. The effects on early postnatal growth and viability were compared to results generated from standard mouse teratology bioassays as reported in the literature (there were nine regimens for which no valid comparisons could be made). The procedure correctly categorized 25 of the 30 treatment regimens which were considered developmentally toxic in the mouse, as well as nine of 11 which were considered to be nondevelopmentally toxic in the mouse. Thus, based upon the criteria used in the present study, the assay correctly classified 83% of the chemicals tested as to their effect in a standard mouse bioassay. The five nonconcurring negative findings were likely due to a combination of pharmacokinetic differences between the studies, as well as to the cessation of dosing on day 12, while critical events of organogenesis are still occurring. The assay achieves the requirements for a teratology screening system, but improved predictability would result from the addition of a lower dose level and extension of the dosing period to include later stages of organogenesis.
Teratogenesis Carcinogenesis and Mutagenesis 12/1986; 7(1):7 - 16.
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ABSTRACT: The effects of acute alterations in maternal health status upon fetal development were assessed following exposure of pregnant CD-1 mice on day 8 of gestation to one of ten chemicals at doses calculated to exert either a low or a moderate degree of maternal lethality. The dams were killed on day 18 of gestation, and the fetuses were examined by routine teratological techniques. The chemicals were cacodylic acid, caffeine, deltamethrin, dinoseb, ethylene bisisothiocyanate sulfide (EBIS), endrin, guthion, kepone, sodium salicylate, and toxaphene. Three (cacodylic acid, EBIS, and kepone) produced dose-related increases in the incidence of dams with completely resorbed litters. Prenatal mortality in litters that contained live fetuses at term was elevated only for one chemical (cacodylic acid). Fetal weight was reduced in three instances (cacodylic acid, endrin, and guthion), while the incidence of terata was markedly elevated for two (cacodylic acid and kepone). For two other chemicals (endrin and sodium salicylate), a low incidence was found of defects that were similar to defects induced by those chemicals in other species. These effects appear to be chemospecific in nature and not the result of some indirect maternal action. Thus, maternal health status, as measured by the incidence of lethality in the treated groups and by the magnitude of maternal weight gain in surviving females, presents no simple explanation for many manifestations of fetal toxicity. However, for seven chemicals (excluding deltamethrin, EBIS, and kepone) an increased incidence of supernumerary ribs was observed. For three of these seven chemicals (caffeine, dinoseb, and toxaphene). supernumerary ribs was the only observed fetal effect. There was a significant linear inverse-relationship between maternal weight gain during gestation and the incidence of extra ribs in the treated groups compared to their respective controls. Under the experimental conditions of this study, it appears that the incidence of supernumerary ribs increased in response to a nonspecific maternal toxicity.
Teratogenesis Carcinogenesis and Mutagenesis 12/1984; 5(1):3 - 13.
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ABSTRACT: Boric acid (BA) has many uses as an industrial compound and is widely distributed in the environment. BA has been shown to produce rib agenesis, a rare effect in laboratory animals. This study was conducted to determine if there is a period of sensitivity to this unusual effect. BA (500 or 750 mg/kg) was administered p.o. to pregnant CD-1 mice once daily on gestational days (GDs) 6-10. A reduction of 13th rib length occurred at both dose levels. BA 400mg/kg was also administered twice daily on GD 6, 7, 8, 9, or 10 or on GDs 6-8. A significant decrease in average fetal weight was observed in all treatment groups. Significant increases in the incidence of cervical ribs/ossifications resulted from treatments on GD 7 and GDs 6-8. Rib agenesis occurred with treatment on GD 8 and GDs 6-8. Reduced rib length, a decreased incidence of supernumerary ribs (SNR), and an increased incidence of fused and/or branched ribs occurred when dams were treated GDs 6-8. Doses of 750 mg/kg given twice on day 8 produced significant increases in several thoracic skeletal anomalies. Further studies of pathogenesis are necessary to determine the earliest perturbations and the processes that are affected. The sensitivity of embryos to treatment on GD 8 to rib agenesis suggests that BA is affecting early processes such as gastrulation and presomitic mesoderm formation and patterning in this area.
Reproductive Toxicology 16(3):237-43. · 3.23 Impact Factor
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ABSTRACT: Supernumerary or accessory ribs (SNR), either lumbar (LR) or cervical (CR), are a common finding in standard developmental toxicology bioassays. The biological significance of these anomalies within the regulatory arena has been problematic and the subject of some debate. In rodents, the spontaneous incidence of SNR is species and strain related and ranges from <1% to >30%. Compound-induced LR are induced by a wide variety of chemical and physical agents when pregnant animals are exposed during specific gestational periods. A significant portion of the agent-induced LR may be due to maternal factors, as it has been shown that stress alone will induce LR in rodents. SNR are not isolated phenomena and signify basic alterations in the architecture of the axial skeleton. LR are associated with longer ribs, increased numbers of vertebrosternal ribs, and the presence of extra presacral vertebrae ("anteriorization"). CR are associated with reduced numbers of vertebrosternal ribs (posteriorization). It is evident that SNR are not a single anomaly, but consist of two unrelated structures: an extra rib that has a cartilaginous segment at the distal end, and an ossification site that lacks cartilage. These have a bimodal size distribution, with the population of extra ribs being significantly longer than the ossification sites, and 0.6 mm can be used as an approximate length for distinguishing the two populations in mice. Extra ribs are permanent structures in contrast to ossification sites that disappear postnatally, probably becoming part of the lateral transverse vertebral processes. SNR are also found in humans although, in contrast to laboratory species, CR are more commonly noted. SNR are associated with adverse heath effects, and CR with inducing thoracic outlet disease characterized by diminished blood flow and altered position of the ganglia and nerve roots in the area of the C7-T1 vertebrae. LR are associated with lower back pain and L4-5 degeneration. The incidence of CR is greatly reduced in adult humans as compared to fetuses, and it has been hypothesized that fetal "SNR" may be largely composed of ossification sites that disappear postnatally. The mechanisms involved in the formation of extra ribs are not understood at this time, although the fact that the early sensitive periods for their initiation during embryogenesis is coupled with the associated changes in the axial skeleton argues for their induction being due to fundamental changes in gene expression. The sum of the experimental evidence supports the idea of SNR being composed of two different structures: extra ribs that are permanent dysmorphological structures that may be induced by xenobiotics and/or maternal stress, and ossification sites that may be transient variations in the formation of the lateral processes of the vertebrae.
Journal of Toxicology and Environmental Health Part B 7(6):437-49. · 4.72 Impact Factor
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ABSTRACT: The transport of mirex and chlordecone (Kepone) across the placenta during late gestation and through the milk during lactation was investigated in the rat. In the placental transport study, doses of 5 mg/kg were administered on Day 15, 18, or 20 of gestation and animals were killed 4, 24, or 48 hr after treatment. Both compounds crossed the placenta and were present in the fetus at all examination times. Maternal tissue levels exceeded fetal tissue levels by a factor of 4 to 5. Slightly higher levels of chlordecone as compared to mirex were found in maternal and fetal tissues. No effects of gestational age at time of treatment or of position of the fetus in the uterus were seen. In the lactation study, doses of 1 or 10 mg/kg/day were administered on Days 2–5 postpartum and pups were killed at intervals up to 12 days after treatment. The secretion of milk appeared to be a major route of elimination for both pesticides for nursing females, and the greater amount of mirex excreted via the milk as compared with chlordecone is in agreement with differences in their reported octanol-water partition coefficients. Initially, mirex entered the milk more rapidly than chlordecone. After cessation of treatment, mirex milk levels fell quickly, but chlordecone levels remained fairly constant. In the pups, mirex tissue levels paralleled milk levels; chlordecone levels, however, continued to increase in the tissues throughout the observation period.
Pesticide Biochemistry and Physiology 14(3):227-235. · 1.71 Impact Factor
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ABSTRACT: The developmental toxicity of the wide-spectrum herbicide bromoxynil (bromoxynil phenol; 3,5-dibromo-4-hydroxyphenyl cyanide) was evaluated in Sprague-Dawley rats and Swiss-Webster mice, and the developmental toxicity of its octanoate ester (2,6-dibromo-4-cyanophenyl octanoate) was evaluated in Sprague-Dawley rats. Animals were treated from Day 6 to Day 15 of gestation [presence of sperm or semen plug = 0 of gestation]. The doses administered were as follows: bromoxynil phenol in the mouse, 342, 114, and 38 μmol/kg/day; bromoxynil phenol and bromoxynil octanoate in the rat, 54, 18, and 6 μmol/kg/day. Some animals were killed on selected days during treatment for measurement of organ weights sensitive to stress. In mice treated with bromoxynil phenol, maternal mortality was noted at 114 and 342 μmol/kg/day, but surviving females gained weight normally. Liver to body weight ratios increased with increasing dose, but no consistent effect was seen on adrenal, thymus, or spleen weights. Fetuses of mice treated with the highest dose of bromoxynil phenol were of lower weight and had a higher incidence of supernumerary ribs than controls. In rats, bromoxynil phenol and its octanoate ester at the highest doses used caused no mortality but resulted in only transient decreases in maternal weight gain and significantly increased the liver to body weight ratio, but did not significantly alter adrenal, thymus, or spleen weight in the dams. No significant maternal effects were seen at lower doses. The highest doses of both compounds increased the incidence of supernumberary ribs in fetuses of treated rats, but did not induce other anomalies. Fetal weight was reduced in rats at the highest dose of bromoxynil octanoate, but no effects on fetal weight were seen with bromoxynil phenol. Bromoxynil exposure produced a high incidence of supernumerary ribs at maternally toxic doses in both rats and mice, although no evidence of maternal stress per se was found. The mechanism and significance of this effect require further study.
Fundamental and Applied Toxicology.
