Revisiting the testicular toxicity of cyanide: Assessment of the new and existing literature.

BACKGROUND: Based on new testing, we re-assess U.S. EPA and California OEHHA conclusions regarding male reproductive toxicity associated with cyanide exposure. METHODS: Literature identified by ATSDR, ECETOC and EPA was complemented by studies conducted after 2006. Relevant studies were scored for quality using ToxRTool. RESULTS: Eleven 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-treatment recovery) and found a smaller decrease in water consumption (11% versus 18% at 300 ppm) and no treatment-related changes in male reproductive measures. Although thyroid/parathyroid weights were increased at 300 ppm, histopathology and thyroid hormone levels were unaffected. The remaining high-quality cyanide studies reported no adverse findings in male reproductive organs. Unconfounded sperm measures were not adversely affected in any quality 1 studies. CONCLUSIONS: Changes in the male reproductive system reported after cyanide exposure in the NTP study were not reproducible, unlikely to be treatment-related, and should not be used as the sole basis for human health assessments.

Systematic assessment of quaternary ammonium compounds for the potential to elicit developmental and reproductive effects.

INTRODUCTION: Quaternary 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. METHODS: A 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. RESULTS: Six studies were scored as "reliable without restriction"; four studies were considered "reliable with restriction" (mainly due to small rabbit group sizes). No test article-related, adverse DART endpoints were reported in these studies. ToxRTool scored the remaining eight studies as "not reliable." The unreliable studies failed to fully describe methods and/or endpoints, did not quantify (and in some cases, did not verify) exposures, utilized non-standard test methods, reported endpoints incorrectly, and assessed endpoints at inappropriate times. Some (not all) unreliable studies reported adverse effects after 7.5 mg QUATs/kg/day (mice), but these results were inconsistent. The reliable studies tested exposures ≥100 mg/kg/day (rats) with no effects. CONCLUSIONS: The available weight of evidence indicates no adverse DART effects after QUATs exposures at anticipated concentrations and normal use.

Estimation of cancer risks and benefits associated with a potential increased consumption of fruits and vegetables.

The current paper provides an analysis of the potential number of cancer cases that might be prevented if half the U.S. population increased its fruit and vegetable consumption by one serving each per day. This number is contrasted with an upper-bound estimate of concomitant cancer cases that might be theoretically attributed to the intake of pesticide residues arising from the same additional fruit and vegetable consumption. The cancer prevention estimates were derived using a published meta-analysis of nutritional epidemiology studies. The cancer risks were estimated using U.S. Environmental Protection Agency (EPA) methods, cancer potency estimates from rodent bioassays, and pesticide residue sampling data from the U.S. Department of Agriculture (USDA). The resulting estimates are that approximately 20,000 cancer cases per year could be prevented by increasing fruit and vegetable consumption, while up to 10 cancer cases per year could be caused by the added pesticide consumption. These estimates have significant uncertainties (e.g., potential residual confounding in the fruit and vegetable epidemiologic studies and reliance on rodent bioassays for cancer risk). However, the overwhelming difference between benefit and risk estimates provides confidence that consumers should not be concerned about cancer risks from consuming conventionally-grown fruits and vegetables.

The placenta, transfer of immunoglobulins, and safety assessment of biopharmaceuticals in pregnancy.

Anatomical and developmental differences of the parental-offspring interface among experimental animals and humans throughout gestation are reviewed focusing on biodistribution of immunoglobulins (IgG). The formation of the extraembryonic membranes, uteroplacental circulation, and characteristics of the placenta (gross shape, modes of implantation, surface modifications that increase surface area, and extent of embryonic invasion into maternal tissue) are reviewed. Placental physiology and function are covered with attention to transfer of xenobiotics. Placental transfer of immunoglobulins in the human, non-human primate (NHP), rodent, and rabbit is discussed and the transfer of human fragment crystallizable (Fc)-containing biopharmaceuticals and potential impact on developmental toxicity risk assessment are specifically addressed. Safety assessment is often limited to the NHP as the only pharmacologically relevant model, despite poor statistical power as employed in current experimental designs. Although data are limited, the gestational timing of placental IgG transfer in rabbits appears to be more consistent with that of humans (i.e. occurring at the very end and after completion of organogenesis) than that of rodents, making the rabbit a reasonable choice assuming it is pharmacologically relevant. The rodent is not considered the most appropriate model for human placental transfer of Fc-containing biopharmaceuticals because it is currently believed to overestimate exposure during organogenesis. Nevertheless, the rodent may provide a conservative approach for hazard identification. It is clear that additional experimentation is needed to further clarify the timing of prenatal transfer of Fc-containing biopharmaceuticals in various species.

Analysis and integration of developmental neurotoxicity and ancillary data into risk assessment: a case study of dimethoate.

Dimethoate is an organophosphate (OP) pesticide used to control a wide variety of insects on agricultural crops and ornamentals. To ensure that dimethoate is used safely, it is important to determine exposure levels that protect against adverse effects at all life stages, including the developing fetus, infant, and child. Based on an analysis of a developmental neurotoxicity (DNT) study, a cholinesterase (ChE) sensitivity study, a cross-fostering study, and several single- and multigenerational reproductive toxicity studies, two potential critical endpoints for dimethoate were identified: brain ChE inhibition (ChEI) in adult females, and pup mortality. An initial evaluation concluded that pup mortality was a preferable endpoint, based on an increased number of pup deaths born to dams dosed with > or =3 mg/kg dimethoate via oral gavage. Closer examination, however, revealed that the pup deaths were clustered in a small number of litters in which the dams providing postnatal care exhibited maternal care deficits. When the data were analyzed using the dam as the unit of statistical significance, a significant increase in the average litter proportion of pup deaths was observed only when the dams were dosed postnatally with 6 mg/kg dimethoate while they were raising the pups. Gestational exposure (i.e., during pregnancy only) to 6 mg/kg dimethoate exerted no effect on pup survival. This leads to the conclusion that it is postnatal exposure of the nursing dams that is associated with pup mortality. Furthermore, a previous benchmark dose (BMD) meta-analysis approach revealed that BMDL(10) for adult females (the lower 95% bound of the dose resulting in a 10% reduction in the parameter of interest) for ChEI was > 3-fold lower than the BMDL(10) for pup mortality (0.19 and 0.68 mg/kg, respectively). Overall, this study underscores the importance of using the dam as the unit of statistical significance when assessing data collected in the perinatal period, and it is concluded that adult brain ChEI is the correct critical endpoint for assessing risk of dimethoate toxicity.

Monomethylarsonic acid and dimethylarsinic acid: developmental toxicity studies with risk assessment.

BACKGROUND: The toxicity of arsenic compounds is highly dependent on the valence and methylation state of the compound. Although there is extensive published literature on the potential developmental toxicity of inorganic arsenic compounds, little exists on organic arsenic compounds and, in particular, studies conducted in accordance with conventional regulatory guidelines appropriate for risk assessment are rare. The organic arsenic compounds, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV, also called cacodylic acid), are the active ingredients in pesticide products that are used mainly for weed control. MMAV and DMAV are also metabolites of inorganic arsenic formed intracellularly by most living organisms (animals, plants and bacteria). In mammals, this occurs predominantly in liver cells. METHODS: Conventional developmental toxicity studies of orally administered MMAV and DMAV in the Sprague-Dawley rat and New Zealand White rabbit were conducted in commercial contract laboratories in the late 1980 s for regulatory compliance. The results of these studies are summarized and presented to broaden the data available in the public domain. RESULTS: In both species, data shows an absence of dose-related effects at organic arsenic exposures that were not maternally toxic. MMAV doses of 0, 10, 100, and 500 mg/kg/day (rat) and 0, 1, 3, 7, and 12 mg/kg/day (rabbit) and DMAV doses of 0, 4, 12, and 36 mg/kg/day (rat) and 0, 3, 12, and 48 mg/kg/day (rabbit) were administered by oral gavage daily during organogenesis (Gestation Day [GD] 6-15, rat; GD 7-19, rabbit) and the litters examined at maternal sacrifice (GD 20, rat; GD 29, rabbit). After treatment with MMAV, maternal and fetal toxicity were observed at the highest doses of 500 mg/kg/day (rat) and 12 mg/kg/day (rabbit), but no treatment-related developmental toxicity at the lower doses, even in the presence of minimal maternal toxicity in the rat at 100 mg/kg/d. There was no evidence of teratogenicity associated with MMAV treatment. With DMAV, maternal and developmental toxicity were observed in the rat at 36 mg/kg/day, with a higher than spontaneous incidence of fetuses with diaphragmatic hernia. In the rabbit at 48 mg/kg/day, there was marked maternal toxicity, culminating for most females in abortion and with no surviving fetuses for evaluation. There was no treatment-related maternal or developmental toxicity in the rat or rabbit at 12 mg/kg/day. Based on pregnancy outcome, the developmental toxicity no observed adverse effect level (NOAEL) for orally administered MMAV were 100 and 7 mg/kg/day in the rat and rabbit, respectively, and for DMAV were 12 mg/kg/day in both species. CONCLUSIONS: Margins of exposure estimated based on conservative estimates of daily intakes of arsenic in all of its forms indicate that exposure to MMAV or DMAV at environmentally relevant exposure levels, by the oral route (the environmentally relevant route of exposure) is unlikely to pose a risk to pregnant women and their offspring.