BackgroundBased on new testing, we re‐assess U.S. EPA and California OEHHA conclusions regarding ... more BackgroundBased on new testing, we re‐assess U.S. EPA and California OEHHA conclusions regarding male reproductive toxicity associated with cyanide exposure.MethodsLiterature identified by ATSDR, ECETOC and EPA was complemented by studies conducted after 2006. Relevant studies were scored for quality using ToxRTool.ResultsEleven pertinent animal investigations were identified; five with quality scores of 1 were evaluated in‐depth. The NTP 13‐week drinking water study of NaCN in rats reported significantly decreased water intakes and reduced cauda epididymal weights; altered sperm parameters occurred in high‐dose rats. When compared to contemporaneous historical control data (HCD), the mean cauda epididymal weights of cyanide‐treated rats in the NTP study were within HCD, whereas control weights exceeded HCD. A new 13‐week drinking water study used the same design with additional features (individually caged rats, “paired water” controls, thyroid hormone determinations, post‐treatmen...
The gastrointestinal (GI) system absorbs nutrients and xenobiotics, excretes waste, and performs ... more The gastrointestinal (GI) system absorbs nutrients and xenobiotics, excretes waste, and performs immunologic and endocrine functions. The subdivisions of the mature gut and the complexity of their corrugated, absorptive luminal surfaces differ greatly among mammals. Regardless, the embryonic gut tube in all mammalian species arises when cephalocaudal folding incorporates the roof of the yolk sac into the embryo. The gut tube quickly lengthens and bulges into the umbilical cord. Upon reentry into the abdominal cavity, the gut tube begins to differentiate-a process that continues until well into the lactation period. Differentiation of the small intestine involves (1) increasing the absorptive surface area of the lumen; (2) establishing mechanisms to control the pH of luminal contents; (3) forming a hierarchical vascular system for distribution of absorbed nutrients; (4) developing a complex enteric nervous system to control motility; (5) providing a system for replenishment of cells; and (6) contributing to the immunity of the organism. Because the length of gestation varies among species typically used in safety tests and is much shorter than human gestation, the state of GI maturation at the time of parturition differs significantly. Differences in GI maturation can contribute to species differences in the rate and extent of absorption; these differences must be considered when designing and interpreting pharmacological/toxicological studies and extrapolating safety test results to humans.
This article reports a standard mouse Embryo-Fetal Developmental Toxicity study with sertraline. ... more This article reports a standard mouse Embryo-Fetal Developmental Toxicity study with sertraline. We are disappointed because the paper presents a weak and tendentious case for labeling this clinically useful drug as a mouse teratogen. Our field no longer labels agents as teratogens in the absence of specific exposure conditions, nor is it acceptable to use this term to describe such a small increase in a common malformation in a rodent species in the presence of maternal toxicity. We list below errors, omissions, and unclear statements that detract from the value of the paper.
IntroductionQuaternary ammonium compounds (QUATs) are commonly found in cleaning products, disinf... more IntroductionQuaternary ammonium compounds (QUATs) are commonly found in cleaning products, disinfectants, hand sanitizers, and personal care products. They have been used for >50 years and are considered safe when used according to directions. Recent papers report reduced fertility and neural tube defects in rodents after low‐level exposures. To determine if QUATs interfere with mammalian reproduction and development, we conducted a methodical assessment of all available data.MethodsA systematic literature search identified 789 potential articles. Review of titles and abstracts found eight relevant studies, including two dissertation chapters; to these, 10 unpublished, guideline‐compliant developmental and reproductive toxicity (DART) studies of QUATs (alkyldimethylbenzylammonium chloride [ADBAC] and dialkyldimethylammonium chloride [DDAC]) were added. ToxRTool was utilized to evaluate all 18 studies for data quality.ResultsSix studies were scored as “reliable without restriction...
Abstract The central nervous system is a highly complex organ with a multifaceted, intricate, yet... more Abstract The central nervous system is a highly complex organ with a multifaceted, intricate, yet orderly development. Similar to other organs, the anlagen of nervous system structures appear and develop in a defined sequence that is remarkably consistent across species and will be briefly reviewed. Nevertheless, the gestational age at which these events occur varies across species. In this chapter, developmental data for the nervous systems of rats, mice, monkeys, and humans are presented in a series of tables based on the appearance of external and internal milestones. The comparative developmental timing for establishing the cerebral cortical layers and myelination of various nervous system tracts is also presented. Such tables identify gestational ages when particular structures develop across species which, in turn, pinpoints the most sensitive period in the animal models for studying the development of nervous system structures. These data are important for designing investigational studies of nervous system development.
The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given b... more The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given black‐box warnings against their use in pregnancy due to potential teratogenic effects. These first‐ and second‐generation retinoids were initially formulated for oral dosing and are structurally very similar to vitamin A, which has beneficial effects on skin as well as plays a vital role in driving healthy embryogenesis. Some of these early retinoids have since been reformulated for topical application, which has resulted in their diminished potential for systemic exposures. Additionally, rational drug design has been applied to create today's third‐generation retinoids (adapalene, tazarotene, and bexarotene). These compounds include aromatic rings within their molecular cores to provide structural rigidity that contrasts with the flexible aliphatic backbone of vitamin A and the earlier generations of retinoids, and thus limits their off‐target activity. As a result of these design features, the teratogenic potential in animals of the third‐generation retinoids and those reformulated for topical use is generally less than seen with oral administration of earlier generations of retinoids. The available, but limited, epidemiologic data further show little‐to‐no teratogenic potential associated with real‐life use of these compounds in humans. Given the paucity of epidemiologic data available at this time, however, it is recommended that the use of topical retinoids during pregnancy be avoided. However, in circumstances when inadvertent exposure in pregnancy may occur, the available data provide some reassurance that adverse pregnancy outcomes are unlikely.
Embryos and tumors share several characteristics, but embryos differ from tumors in their coordin... more Embryos and tumors share several characteristics, but embryos differ from tumors in their coordination of cellular-and tissue-level processes, including organized differentiation, remodeling of tissues through apoptosis, and disciplined migrations of cells. Embryonic cellular events are kept on track through orderly cell-cell communication via signal transduction pathways. If the path-Based on the 2014 Narsingh Agnish Lecture presented at the 54th Annual Meeting of the Teratology Society.
Background: Trichloroethylene (TCE) was negative for developmental toxicity after inhalation and ... more Background: Trichloroethylene (TCE) was negative for developmental toxicity after inhalation and oral gavage exposure of pregnant rats but fetal cardiac defects were reported following drinking water exposure throughout gestation. Because of the deficiencies in this latter study, we performed another drinking water study to evaluate whether TCE causes heart defects. Methods: Groups of 25 mated Sprague Dawley rats consumed water containing 0, 0.25, 1.5, 500, or 1,000 ppm TCE from gestational day 1-21. TCE concentrations were measured at daily formulation, when placed into water bottles each day and when water bottles were removed from cages. Four additional mated rats per group were used for plasma measurements. At termination, fetal hearts were carefully dissected fresh and examined. Results: All TCE concentrations were >90% of target when initially placed in water bottles and when bottles were placed on cages. All dams survived with no clinical signs. Rats in the two higher dose groups consumed less water/day than other groups but showed no changes in maternal or fetal weights. The only fetal cardiac observation was small (<1 mm) membranous ventricular septal defect occurring in all treated and water control groups; incidences were within the range of published findings for naive animals. TCE was not detected in maternal blood, but systemic exposure was confirmed by detecting its primary oxidative metabolite, trichloroacetic acid, although only at levels above the quantitation limit in the two higher dose groups. Conclusions: Ingesting TCE in drinking water ≤1,000 ppm throughout gestation does not cause cardiac defects in rat offspring.
AimsWe assessed the animal and epidemiological data to determine if chloroform exposure causes de... more AimsWe assessed the animal and epidemiological data to determine if chloroform exposure causes developmental and/or reproductive toxicity.Results and DiscussionInitial scoping identified developmental toxicity as the primary area of concern. At levels producing maternal toxicity in rats and mice, chloroform caused decrements in fetal weights and associated delays in ossification. In a single mouse inhalation study, exposure to a high concentration of chloroform was associated with small fetuses and increased cleft palate. However, oral exposure of mice to chloroform at a dose 4 times higher was negative for cleft palate; multiple inhalation studies in rats were also negative. Epidemiologic data on low birth weight and small for gestational age were generally equivocal, preventing conclusions from being drawn for humans. The animal data also show evidence of very early (peri‐implantation) total litter losses at very high exposure levels. This effect is likely maternally mediated rath...
Conflicting views on the potential carcinogenicity of glyphosate: how did we get here and what sh... more Conflicting views on the potential carcinogenicity of glyphosate: how did we get here and what should we do?
BackgroundBased on new testing, we re‐assess U.S. EPA and California OEHHA conclusions regarding ... more BackgroundBased on new testing, we re‐assess U.S. EPA and California OEHHA conclusions regarding male reproductive toxicity associated with cyanide exposure.MethodsLiterature identified by ATSDR, ECETOC and EPA was complemented by studies conducted after 2006. Relevant studies were scored for quality using ToxRTool.ResultsEleven pertinent animal investigations were identified; five with quality scores of 1 were evaluated in‐depth. The NTP 13‐week drinking water study of NaCN in rats reported significantly decreased water intakes and reduced cauda epididymal weights; altered sperm parameters occurred in high‐dose rats. When compared to contemporaneous historical control data (HCD), the mean cauda epididymal weights of cyanide‐treated rats in the NTP study were within HCD, whereas control weights exceeded HCD. A new 13‐week drinking water study used the same design with additional features (individually caged rats, “paired water” controls, thyroid hormone determinations, post‐treatmen...
The gastrointestinal (GI) system absorbs nutrients and xenobiotics, excretes waste, and performs ... more The gastrointestinal (GI) system absorbs nutrients and xenobiotics, excretes waste, and performs immunologic and endocrine functions. The subdivisions of the mature gut and the complexity of their corrugated, absorptive luminal surfaces differ greatly among mammals. Regardless, the embryonic gut tube in all mammalian species arises when cephalocaudal folding incorporates the roof of the yolk sac into the embryo. The gut tube quickly lengthens and bulges into the umbilical cord. Upon reentry into the abdominal cavity, the gut tube begins to differentiate-a process that continues until well into the lactation period. Differentiation of the small intestine involves (1) increasing the absorptive surface area of the lumen; (2) establishing mechanisms to control the pH of luminal contents; (3) forming a hierarchical vascular system for distribution of absorbed nutrients; (4) developing a complex enteric nervous system to control motility; (5) providing a system for replenishment of cells; and (6) contributing to the immunity of the organism. Because the length of gestation varies among species typically used in safety tests and is much shorter than human gestation, the state of GI maturation at the time of parturition differs significantly. Differences in GI maturation can contribute to species differences in the rate and extent of absorption; these differences must be considered when designing and interpreting pharmacological/toxicological studies and extrapolating safety test results to humans.
This article reports a standard mouse Embryo-Fetal Developmental Toxicity study with sertraline. ... more This article reports a standard mouse Embryo-Fetal Developmental Toxicity study with sertraline. We are disappointed because the paper presents a weak and tendentious case for labeling this clinically useful drug as a mouse teratogen. Our field no longer labels agents as teratogens in the absence of specific exposure conditions, nor is it acceptable to use this term to describe such a small increase in a common malformation in a rodent species in the presence of maternal toxicity. We list below errors, omissions, and unclear statements that detract from the value of the paper.
IntroductionQuaternary ammonium compounds (QUATs) are commonly found in cleaning products, disinf... more IntroductionQuaternary ammonium compounds (QUATs) are commonly found in cleaning products, disinfectants, hand sanitizers, and personal care products. They have been used for >50 years and are considered safe when used according to directions. Recent papers report reduced fertility and neural tube defects in rodents after low‐level exposures. To determine if QUATs interfere with mammalian reproduction and development, we conducted a methodical assessment of all available data.MethodsA systematic literature search identified 789 potential articles. Review of titles and abstracts found eight relevant studies, including two dissertation chapters; to these, 10 unpublished, guideline‐compliant developmental and reproductive toxicity (DART) studies of QUATs (alkyldimethylbenzylammonium chloride [ADBAC] and dialkyldimethylammonium chloride [DDAC]) were added. ToxRTool was utilized to evaluate all 18 studies for data quality.ResultsSix studies were scored as “reliable without restriction...
Abstract The central nervous system is a highly complex organ with a multifaceted, intricate, yet... more Abstract The central nervous system is a highly complex organ with a multifaceted, intricate, yet orderly development. Similar to other organs, the anlagen of nervous system structures appear and develop in a defined sequence that is remarkably consistent across species and will be briefly reviewed. Nevertheless, the gestational age at which these events occur varies across species. In this chapter, developmental data for the nervous systems of rats, mice, monkeys, and humans are presented in a series of tables based on the appearance of external and internal milestones. The comparative developmental timing for establishing the cerebral cortical layers and myelination of various nervous system tracts is also presented. Such tables identify gestational ages when particular structures develop across species which, in turn, pinpoints the most sensitive period in the animal models for studying the development of nervous system structures. These data are important for designing investigational studies of nervous system development.
The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given b... more The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given black‐box warnings against their use in pregnancy due to potential teratogenic effects. These first‐ and second‐generation retinoids were initially formulated for oral dosing and are structurally very similar to vitamin A, which has beneficial effects on skin as well as plays a vital role in driving healthy embryogenesis. Some of these early retinoids have since been reformulated for topical application, which has resulted in their diminished potential for systemic exposures. Additionally, rational drug design has been applied to create today's third‐generation retinoids (adapalene, tazarotene, and bexarotene). These compounds include aromatic rings within their molecular cores to provide structural rigidity that contrasts with the flexible aliphatic backbone of vitamin A and the earlier generations of retinoids, and thus limits their off‐target activity. As a result of these design features, the teratogenic potential in animals of the third‐generation retinoids and those reformulated for topical use is generally less than seen with oral administration of earlier generations of retinoids. The available, but limited, epidemiologic data further show little‐to‐no teratogenic potential associated with real‐life use of these compounds in humans. Given the paucity of epidemiologic data available at this time, however, it is recommended that the use of topical retinoids during pregnancy be avoided. However, in circumstances when inadvertent exposure in pregnancy may occur, the available data provide some reassurance that adverse pregnancy outcomes are unlikely.
Embryos and tumors share several characteristics, but embryos differ from tumors in their coordin... more Embryos and tumors share several characteristics, but embryos differ from tumors in their coordination of cellular-and tissue-level processes, including organized differentiation, remodeling of tissues through apoptosis, and disciplined migrations of cells. Embryonic cellular events are kept on track through orderly cell-cell communication via signal transduction pathways. If the path-Based on the 2014 Narsingh Agnish Lecture presented at the 54th Annual Meeting of the Teratology Society.
Background: Trichloroethylene (TCE) was negative for developmental toxicity after inhalation and ... more Background: Trichloroethylene (TCE) was negative for developmental toxicity after inhalation and oral gavage exposure of pregnant rats but fetal cardiac defects were reported following drinking water exposure throughout gestation. Because of the deficiencies in this latter study, we performed another drinking water study to evaluate whether TCE causes heart defects. Methods: Groups of 25 mated Sprague Dawley rats consumed water containing 0, 0.25, 1.5, 500, or 1,000 ppm TCE from gestational day 1-21. TCE concentrations were measured at daily formulation, when placed into water bottles each day and when water bottles were removed from cages. Four additional mated rats per group were used for plasma measurements. At termination, fetal hearts were carefully dissected fresh and examined. Results: All TCE concentrations were >90% of target when initially placed in water bottles and when bottles were placed on cages. All dams survived with no clinical signs. Rats in the two higher dose groups consumed less water/day than other groups but showed no changes in maternal or fetal weights. The only fetal cardiac observation was small (<1 mm) membranous ventricular septal defect occurring in all treated and water control groups; incidences were within the range of published findings for naive animals. TCE was not detected in maternal blood, but systemic exposure was confirmed by detecting its primary oxidative metabolite, trichloroacetic acid, although only at levels above the quantitation limit in the two higher dose groups. Conclusions: Ingesting TCE in drinking water ≤1,000 ppm throughout gestation does not cause cardiac defects in rat offspring.
AimsWe assessed the animal and epidemiological data to determine if chloroform exposure causes de... more AimsWe assessed the animal and epidemiological data to determine if chloroform exposure causes developmental and/or reproductive toxicity.Results and DiscussionInitial scoping identified developmental toxicity as the primary area of concern. At levels producing maternal toxicity in rats and mice, chloroform caused decrements in fetal weights and associated delays in ossification. In a single mouse inhalation study, exposure to a high concentration of chloroform was associated with small fetuses and increased cleft palate. However, oral exposure of mice to chloroform at a dose 4 times higher was negative for cleft palate; multiple inhalation studies in rats were also negative. Epidemiologic data on low birth weight and small for gestational age were generally equivocal, preventing conclusions from being drawn for humans. The animal data also show evidence of very early (peri‐implantation) total litter losses at very high exposure levels. This effect is likely maternally mediated rath...
Conflicting views on the potential carcinogenicity of glyphosate: how did we get here and what sh... more Conflicting views on the potential carcinogenicity of glyphosate: how did we get here and what should we do?
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