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Abstract: Cobalt (Co) is an essential element in humans as a component of vitamin B12. However, at high levels Co exposure has been shown to have detrimental effects. This study was designed to identify a chronic oral reference dose (RfD) for Co. Currently available data indicate that non-cancer health effects associated with Co exposure may include hematological, neurological, immunological, reproductive, cardiovascular, and endocrine responses. This analysis employs the standard US EPA risk assessment methodology for establishing a chronic RfD. In this analysis, the Jaimet and Thode (1955) 10-week, multiple dose human study of thyroid effects (decreased iodine uptake) in children was determined to be the most robust and sensitive study for identifying a potential point of departure dose (POD). A dose of 0.9mgCo/kg-day was chosen as the POD. Consistent with the US EPA’s previous derivation of the perchlorate RfD, which is also based on decreased iodine uptake in humans, we considered several uncertainly factors (UFs), and determined that a factor of 10 for human variability was appropriate, as well as a factor of three for database adequacy. Applying an aggregate uncertainty factor of 30 to the POD yields a chronic oral RfD of 0.03mg/kg-day. We believe this value would be protective of non-cancer health effects in the general population for a lifetime of daily exposure to Co. [Copyright &y& Elsevier]

Abstract: Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood-brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe-depleted diet for 4weeks. FeD and FeO treatment resulted in a significant increase (+55%) and decrease (−56%) in CSF Cu levels (p<0.05), respectively; however, neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+92%) and significantly slower (−53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p<0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF. [Copyright &y& Elsevier]

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard. • Human exposure to cobalt occurs through multiple sources including medical devices. • A weight of evidence evaluation of cobalt reproductive toxicity was performed. • Reproductive responses to Co limited to concentrations/doses above MTD. • Cobalt exposure from medical devices does not present a reproductive hazard. [ABSTRACT FROM AUTHOR]

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard. • A weight-of-evidence assessment of long-term rodent carcinogenicity and tumor initiation/promotion studies was performed. • No increases in tumor incidence were observed or responses were not relevant to human hazard identification. • Qualitative assessment and quantitative simulations confirm relevance of rodent model data to humans. • Results demonstrate that acetaminophen is not a carcinogenicity hazard. [ABSTRACT FROM AUTHOR]

Abstract: The choroid plexus, a barrier between the blood and cerebrospinal fluid (CSF), is known to accumulate lead (Pb) and also possibly function to maintain brain''s homeostasis of Aβ, an important peptide in the etiology of Alzheimer''s disease. This study was designed to investigate if Pb exposure altered Aβ levels at the blood–CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hours later, a FAM-labeled Aβ (200 pmol) was infused into the lateral ventricle and the plexus tissues were removed to quantify Aβ accumulation. Results revealed a significant increase in intracellular Aβ accumulation in the Pb-exposed animals compared to controls (p <0.001). When choroidal epithelial Z310 cells were treated with 10 μM Pb for 24 h and 48 h, Aβ (2 μM in culture medium) accumulation was significantly increased by 1.5 fold (p <0.05) and 1.8 fold (p <0.05), respectively. To explore the mechanism, we examined the effect of Pb on low-density lipoprotein receptor protein-1 (LRP1), an intracellular Aβ transport protein. Following acute Pb exposure with the aforementioned dose regimen, levels of LRP1 mRNA and proteins in the choroid plexus were decreased by 35% (p <0.05) and 31.8% (p <0.05), respectively, in comparison to those of controls. In Z310 cells exposed to 10 μM Pb for 24 h and 48 h, a 33.1% and 33.4% decrease in the protein expression of LRP1 was observed (p <0.05), respectively. Knocking down LRP1 resulted in even more substantial increases of cellular accumulation of Aβ, from 31% in cells without knockdown to 72% in cells with LRP1 knockdown (p <0.05). Taken together, these results suggest that the acute exposure to Pb results in an increased accumulation of intracellular Aβ in the choroid plexus; the effect appears to be mediated, at least in part, via suppression of LRP1 production following Pb exposure. [Copyright &y& Elsevier]

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death – thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities. • Mechanisms associated with acetaminophen liver toxicity were evaluated for evidence of carcinogenic potential. • Regardless of dose, the mode of action for acetaminophen does not lead to carcinogenesis. • After supratherapeutic and acute overdoses mechanistic events lead to cell death before carcinogenic transformation occurs. • Results are consistent with the lack of carcinogenic effect in humans and rodents. [ABSTRACT FROM AUTHOR]

In 2019, the California Office of Environmental Health Hazard Assessment initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of its genotoxicity. The objective of this analysis was to inform this review process with a weight-of-evidence assessment of more than 65 acetaminophen genetic toxicology studies that are of widely varying quality and conformance to accepted standards and relevance to humans. In these studies, acetaminophen showed no evidence of induction of point or gene mutations in bacterial and mammalian cell systems or in in vivo studies. In reliable, well-controlled test systems, clastogenic effects were only observed in unstable, p53-deficient cell systems or at toxic and/or excessively high concentrations that adversely affect cellular processes (e.g., mitochondrial respiration) and cause cytotoxicity. Across the studies, there was no clear evidence that acetaminophen causes DNA damage in the absence of toxicity. In well-controlled clinical studies, there was no meaningful evidence of chromosomal damage. Based on this weight-of-evidence assessment, acetaminophen overwhelmingly produces negative results (i.e., is not a genotoxic hazard) in reliable, robust high-weight studies. Its mode of action produces cytotoxic effects before it can induce the stable, genetic damage that would be indicative of a genotoxic or carcinogenic hazard. • Acetaminophen genotoxicity reviewed using weight of evidence approaches. • No induction of gene mutations in bacteria or mammalian cells in vitro or in vivo. • No clastogenicity in robust systems at non-cytotoxic concentrations up to 1 mM in vitro. • No evidence of clastogenicity in well-controlled human studies even at acute overdose. • Does not induce genetic damage indicative of a genotoxic or carcinogenic hazard. [ABSTRACT FROM AUTHOR]