Estimating the incidence of COVID-19, influenza and respiratory syncytial virus infection in three regions of Queensland, Australia, winter 2022: findings from a novel longitudinal testing-based sentinel surveillance programme.

OBJECTIVE: The 2022 Australian winter was the first time that COVID-19, influenza and respiratory syncytial virus (RSV) were circulating in the population together, after two winters of physical distancing, quarantine and borders closed to international travellers. We developed a novel surveillance system to estimate the incidence of COVID-19, influenza and RSV in three regions of Queensland, Australia. DESIGN: We implemented a longitudinal testing-based sentinel surveillance programme. Participants were provided with self-collection nasal swabs to be dropped off at a safe location at their workplace each week. Swabs were tested for SARS-CoV-2 by PCR. Symptomatic participants attended COVID-19 respiratory clinics to be tested by multiplex PCR for SARS-CoV-2, influenza A and B and RSV. Rapid antigen test (RAT) results reported by participants were included in the analysis. SETTING AND PARTICIPANTS: Between 4 April 2022 and 3 October 2022, 578 adults were recruited via their workplace. Due to rolling recruitment, withdrawals and completion due to positive COVID-19 results, the maximum number enrolled in any week was 423 people. RESULTS: A total of 4290 tests were included. Participation rates varied across the period ranging from 25.9% to 72.1% of enrolled participants. The total positivity of COVID-19 was 3.3%, with few influenza or RSV cases detected. Widespread use of RAT may have resulted in few symptomatic participants attending respiratory clinics. The weekly positivity rate of SARS-CoV-2 detected during the programme correlated with the incidence of notified cases in the corresponding communities. CONCLUSION: This testing-based surveillance programme could estimate disease trends and be a useful tool in settings where testing is less common or accessible. Difficulties with recruitment meant the study was underpowered. The frontline sentinel nature of workplaces meant participants were not representative of the general population but were high-risk groups providing early warning of disease.

Thiamethoxam induced mouse liver tumors and their relevance to humans. Part 2: species differences in response.

Thiamethoxam is a neonicotinoid insecticide that is not a mutagen, but it did cause a significant increase in liver cancer in mice, but not rats, in chronic dietary feeding studies. Previous studies in mice have characterized a carcinogenicity mode of action that involved depletion of plasma cholesterol, cell death, both as single cell necrosis and as apoptosis, and sustained increases in cell replication rates. In a study reported in this article, female rats have been exposed to thiamethoxam in their diet at concentrations of 0, 1000, and 3000 ppm for 50 weeks, a study design directly comparable to the mouse study in which the mode of action changes were characterized. In rats, thiamethoxam had no adverse effects on either the biochemistry or histopathology of the liver at any time point during the study. Cell replication rates were not increased, in fact they were significantly decreased at several time points. The lack of effect on the rat liver is entirely consistent with the lack of liver tumor formation in the two-year cancer bioassay. Comparisons of the metabolism of thiamethoxam in rats and mice have shown that concentrations of the parent chemical were either similar or higher in rat blood than in mouse blood in both single dose and the dietary studies strongly indicating that thiamethoxam itself is unlikely to play a role in the development of liver tumors. In contrast, the concentrations of the two metabolites, CGA265307 and CGA330050, shown to play a role in the development of liver damage in the mouse, were 140- (CGA265307) and 15- (CGA330050) fold lower in rats than in mice following either a single oral dose, or dietary administration of thiamethoxam for up to 50 weeks. Comparisons of the major metabolic pathways of thiamethoxam in vitro using mouse, rat, and human liver fractions have shown that metabolic rates in humans are lower than those in the rat suggesting that thiamethoxam is unlikely to pose a hazard to humans exposed to this chemical at the low concentrations found in the environment or during its use as an insecticide.

Case study: weight of evidence evaluation of the human health relevance of thiamethoxam-related mouse liver tumors.

Thiamethoxam (CGA293343; 3-(2-chloro-thiazol-5-ylmethyl)-5-methyl-[1,3,5]oxadiazinan-4-ylidene-N-nitroamine) was shown to increase the incidence of mouse liver tumors in an 18-month study; however, thiamethoxam was not hepatocarcinogenic in rats. Thiamethoxam is not genotoxic, and, given the late life generation of mouse liver tumors, suggests a time-related progression of key hepatic events that leads to the tumors. These key events were identified in a series of studies of up to 50 weeks that showed the time-dependent evolution of relatively mild liver dysfunction within 10 weeks of dosing, followed by frank signs of hepatotoxicity after 20 weeks, leading to cellular attrition and regenerative hyperplasia. A metabolite, CGA330050, was identified as generating the mild hepatic toxicity, and another metabolite, CGA265307, exacerbated the initial toxicity by inhibiting inducible nitric oxide synthase. This combination of metabolite-generated hepatotoxicity and increase in cell replication rates is postulated as the mode of action for thiamethoxam-related mouse liver tumors. The relevance of these mouse-specific tumors to human health was assessed by using the framework and decision logic developed by ILSI-RSI. The postulated mode of action was tested against the Hill criteria and found to fulfill the comprehensive requirements of strength, consistency, specificity, temporality, dose-response, and the collective criteria of being a plausible mode of action that fits with known and similar modes of action. Whereas the postulated mode of action could theoretically operate in human liver, quantitation of the key metabolites in vivo and in vitro showed that mice, but not rats or humans, generate sufficient amounts of these metabolites to initiate the hepatic toxicity and consequent tumors. Indeed, rats fed 3000 ppm thiamethoxam for a lifetime did not develop hepatotoxicity or tumors. In conclusion, the coherence and extent of the database clearly demonstrates the mode of action for mouse liver tumorigenesis and also allows for the conclusion that thiamethoxam does not pose a carcinogenic risk to humans.

Thiamethoxam induced mouse liver tumors and their relevance to humans. Part 1: mode of action studies in the mouse.

Thiamethoxam, a neonicotinoid insecticide, which is not mutagenic either in vitro or in vivo, caused an increased incidence of liver tumors in mice when fed in the diet for 18 months at concentrations in the range 500 to 2500 ppm. A number of dietary studies of up to 50 weeks duration have been conducted in order to identify the mode of action for the development of the liver tumors seen at the end of the cancer bioassay. Both thiamethoxam and its major metabolites have been tested in these studies. Over the duration of a 50-week thiamethoxam dietary feeding study in mice, the earliest change, within one week, is a marked reduction (by up to 40%) in plasma cholesterol. This was followed 10 weeks later by evidence of liver toxicity including single cell necrosis and an increase in apoptosis. After 20 weeks there was a significant increase in hepatic cell replication rates. All of these changes persisted from the time they were first observed until the end of the study at 50 weeks. They occurred in a dose-dependent manner and were only observed at doses (500, 1250, 2500 ppm) where liver tumors were increased in the cancer bioassay. There was a clear no-effect level of 200 ppm. The changes seen in this study are consistent with the development of liver cancer in mice and form the basis of the mode of action. When the major metabolites of thiamethoxam, CGA322704, CGA265307, and CGA330050 were tested in dietary feeding studies of up to 20 weeks duration, only metabolite CGA330050 induced the same changes as those seen in the liver in the thiamethoxam feeding study. It was concluded that thiamethoxam is hepatotoxic and hepatocarcinogenic as a result of its metabolism to CGA330050. Metabolite CGA265307 was also shown to be an inhibitor of inducible nitric oxide synthase and to increase the hepatotoxicity of carbon tetrachloride. It is proposed that CGA265307, through its effects on nitric oxide synthase, exacerbates the toxicity of CGA330050 in thiamethoxam treated mice.

Review of studies concerning the tumorigenicity of 2-butoxyethanol in B6C3F1 mice and its relevance for human risk assessment.

The U.S. National Toxicology Program (NTP) has completed 2-yr inhalation exposures in rats and mice with 2-butoxyethanol (BE). This review concerns the most significant findings from those studies and describes recent research into the mechanistic aspects of BE-mediated tumorigenesis in the mouse and the relevance of such effects to humans. Two tumor types were increased in B6C3F1 mice leading to the classification of "some evidence" of carcinogenicity: liver hemangiosarcomas in male mice and forestomach tumors in female mice (primarily benign papillomas). The results of research collected to date indicate that the tumorigenesis noted for BE was produced by indirect mechanisms. In particular, the occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to red blood cell hemolysis and iron deposition in this organ. Oral administration of BE in mice up to 600 mg/kg/d for up to 90 d produces a dose-related increase in iron (Perl's staining) in Kupffer cells and hepatocytes, increased DNA synthesis in endothelial cells, and enhanced oxidative damage. Further, iron alone, and not BE or BAA, is responsible for producing oxidative damage in cultured hepatocytes from rats or mice. Forestomach neoplasms in female mice were most likely a result of prolonged exposure-induced irritation with compensatory hyperplasia and subsequent tumor promotion. This mechanism is supported by studies indicating elevated levels of BE and BAA in the mouse forestomach tissues and stomach contents following multiple routes of exposure, forestomach epithelial cell cytotoxicity and cell proliferation following administration of BE and BAA, and the increased capacity of forestomach tissues from female mice to metabolize BE to the more irritating metabolite, BAA. The current article summarizes the results of a number of in vivo and in vitro studies designed to elucidate the underlying mechanisms of tumorigenesis by BE in the mouse and discusses the relevance of these for human risk.

Increased formic acid excretion and the development of kidney toxicity in rats following chronic dosing with trichloroethanol, a major metabolite of trichloroethylene.

The chronic toxicity of trichloroethanol, a major metabolite of trichloroethylene, has been assessed in male Fischer rats (60 per group) given trichloroethanol in drinking water at concentrations of 0, 0.5 and 1.0 g/l for 52 weeks. The rats excreted large amounts of formic acid in urine reaching a maximum after 12 weeks ( approximately 65 mg/24 h at 1 g/l) and thereafter declining to reach an apparent steady state at 40 weeks (15-20 mg/24 h). Urine from treated rats was more acidic throughout the study and urinary methylmalonic acid and plasma N-methyltetrahydrofolate concentrations were increased, indicating an acidosis, vitamin B12 deficiency and impaired folate metabolism, respectively. The rats treated with trichloroethanol developed kidney damage over the duration of the study which was characterised by increased urinary NAG activity, protein excretion (from 4 weeks), increased basophilia, protein accumulation and tubular damage (from 12 to 40 weeks), increased cell replication (at week 28) and evidence in some rats of focal proliferation of abnormal tubules at 52 weeks. It was concluded that trichloroethanol, the major metabolite of trichloroethylene, induced nephrotoxicity in rats as a result of formic acid excretion and acidosis.

Absorption, bioavailability, and metabolism of para-nonylphenol in the rat.

To better interpret the responses to para-nonylphenol (NP; CASRN84852-15-3) in in vivo toxicity studies, including estrogen-like activity, the bioavailability of 14C-radiolabelled NP has been determined in male and female CD rats following either single oral doses of 10 and 100 mg/kg, single i.v. doses of 10 mg/kg, or repeated daily oral doses of 10 mg/kg for up to 14 d. Up to 80% of an oral dose of NP was rapidly absorbed, the remainder being excreted unchanged in faeces. Excretion was largely complete within 24 h of dosing. Following absorption, NP was metabolised in the liver, with the majority of the metabolites excreted in bile, mainly as glucuronide conjugates. Unchanged NP was found only in bile and urine from female rats given a 100 mg/kg dose, indicating that metabolic saturation occurred. Following repeated dosing, steady state was reached within 7 d. There was no evidence of significant accumulation into tissue compartments nor of a significant change in clearance or the metabolite profiles in urine. These data suggest that the estrogen-like effects observed in toxicity studies with female rats at oral NP doses of approximately 50 mg/kg/d and greater are a result of the increased bioavailability of NP which occurs following metabolic saturation.

Assessing the health risks following environmental exposure to hexachlorobutadiene.

Hexachloro-1,3-butadiene (HCBD) has been reported to be toxic to the rat kidney in a 2 year study at doses higher than 0.2 mg/kg/day. The toxicity is known to be a consequence of the metabolism of HCBD by glutathione conjugation and the renal beta-lyase pathway. Neither toxicity data, nor data on the metabolism of HCBD, are available in humans. In the current work, the potential of HCBD to cause kidney damage in humans environmentally exposed to this chemical has been assessed quantitatively by comparing the key metabolic steps in rats and humans. To that end, the hepatic conjugation of HCBD with glutathione, the metabolism of the cysteine conjugate by renal beta-lyases and N-acetyltransferases, and the metabolism of the N-acetylcysteine conjugate by renal acylases has been compared in vitro in rat and human tissues. Rates for each metabolic step were lower in humans than in rats; 5-fold for glutathione conjugation, 3-fold for beta-lyase and 3.5-fold for N-acetyltransferase. Acylase activity could not be detected in human kidney cytosol. Use of these data in a physiologically based toxicokinetic model to quantify metabolism by the beta-lyase pathway demonstrated that metabolism in humans was an order of magnitude lower than that in rats. At the no effect level for kidney toxicity in the rat the concentration of beta-lyase metabolites was calculated by the model to be 137.7 mg/l. In humans the same concentration would be achieved following exposure to 1.41 ppm HCBD. This is in contrast to the figure of 0.6 ppb which is obtained when it is assumed that the risk is associated with the internal dose of HCBD itself rather than beta-lyase metabolites.

Physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry of organic esters: assessing the state-of-knowledge and risk assessment applications with methyl methacrylate and vinyl acetate.

Mathematical models have been developed to describe nasal epithelial tissue dosimetry with two compounds, vinyl acetate (VA) and methyl methacrylate (MMA), that cause toxicity in these tissues These models couple computational fluid dynamics (CFD) calculations that map airflow patterns within the nose with physiologically based pharmacokinetic (PBPK) models that integrate diffusion, metabolism, and tissue interactions of these compounds. Dose metrics estimated in these models for MMA and VA, respectively, were rates of MMA metabolism per volume of tissue and alterations in pH in target tissues associated with VA hydrolysis and metabolism. In this article, four scientists who have contributed significantly to development of these models describe the many similarities and relatively few differences between the MMA and VA models. Some differences arise naturally because of differences in target tissues, in the calculated measures of tissue dose, and in the modes of action for highly extracted vapors (VA) compared with poorly extracted vapors (MMA). A difference in the approach used to estimate metabolic parameters from human tissues provides insights into interindividual extrapolation and identifies opportunities for studies with human nasal tissues to enhance current risk assessments. In general, the differences in model structure for these two esters were essential for describing the biology of the observed responses and in accounting for the different measures of target tissue dose. This article is intended to serve as a guide for understanding issues of optimum model structure and optimal data sources for these nasal tissue dosimetry models. We also hope that it leads to greater international acceptance of these hybrid CFD/PBPK modeling approaches for improving risk assessment for many nasal toxicants. In general, these models predict either equivalent (VA) or lower (MMA) nasal tissue doses in humans compared with tissue doses at equivalent exposure concentrations in rats.

The development of forestomach tumours in the mouse following exposure to 2-butoxyethanol by inhalation: studies on the mode of action and relevance to humans.

2-Butoxyethanol, a forestomach carcinogen in mice exposed by inhalation, has been shown to enter the forestomach as a result of grooming and ingestion of material condensed on the skin and fur during exposure. The material entering the stomach concentrates in the forestomach region and persists for at least 48 h post-exposure. Mice given single oral doses of either 2-butoxyethanol or 2-butoxyacetic acid, daily for 10 days, developed a marked hyperkeratosis in the forestomach. 2-Butoxyacetic acid was more potent than 2-butoxyethanol, the NOEL for the former being 50 mg/kg and for the latter, 150 mg/kg. Although a dose dependent increase in cell replication was also seen with both chemicals, the results were confounded by a high labelling rate in the controls. There was no evidence of significant binding of radiolabelled 2-butoxyethanol to proteins in stomach tissues. 2-Butoxyethanol was metabolised in vitro in both mouse and rat forestomach and glandular stomach fractions by alcohol dehydrogenases forming 2-butoxyacetaldehyde which was rapidly converted by aldehyde dehydrogenases to 2-butoxyacetic acid. There was a marked species difference in alcohol dehydrogenase activity between rats and mice with the maximum rates up to one order of magnitude greater in mouse than rat. The alcohol and aldehyde dehydrogenases were heavily concentrated in the stratified squamous epithelium of the forestomach of both rats and mice whereas in the glandular stomach the distribution was more diffuse. In human stomach both enzymes were evenly distributed throughout the epithelial cells of the mucosa. It is concluded that 2-butoxyethanol is ingested following inhalation exposure and concentrates in the forestomach where it is metabolised to 2-butoxyacetic acid which causes cellular damage, increased cell replication and hyperkeratosis. These changes are believed to lead to the tumours seen in mice exposed to 2-butoxyethanol for a lifetime. Differences in structure and enzyme distribution between the rodent and human stomach suggest that the responses seen in the mouse are unlikely to occur in humans.

Direct comparison of the nature of mouse and human GST T1-1 and the implications on dichloromethane carcinogenicity.

Dichloromethane (DCM) is a hepatic and pulmonary carcinogen in mice exposed to high doses by inhalation. It has been shown previously that the incidence of liver and lung tumors does not increase in rats or hamsters exposed to the dihaloalkane under conditions similar to those that produced tumors in mice. The biological consequences of DCM exposure to humans is therefore uncertain. The carcinogenic effects of DCM in the mouse are caused by the interaction with DNA of a glutathione (GSH) conjugate that is produced by the class theta glutathione S-transferase T1-1 (GST T1-1). The species specificity is thought to be due to the greater amount of transferase activity in mouse target organs and specific nuclear localization of GST T1-1 in target cells. This paper directly compares the relative capacity and locality of DCM activation in mouse and human tissues. The results show that mouse GST T1-1 is more efficient in catalyzing the conjugation of DCM with GSH than the orthologous human enzyme. In addition, the mouse expresses higher levels of the transferase than humans in hepatic tissue. Histochemical analysis confirmed the presence of GST T1-1 in the nucleus of mouse liver cells. However, in human liver GST T1-1 was detected in bile duct epithelial cells and hepatocyte nuclei but was also present in the cytoplasm. Taking this information into account, it is unlikely that humans have a sufficiently high capacity to activate DCM for this compound to be considered to represent a carcinogenic risk.