International Programme On Chemical Safety Research Articles

Evaluation of the mode of action and human relevance of liver tumors in male mice treated with epyrifenacil

Epyrifenacil (trademark name: Rapidicil®), a novel protoporphyrinogen oxidase (PPO)-inhibiting herbicide, induces hepatocellular adenomas and carcinomas in male CD-1 mice after 78 weeks treatment. The mode of action (MOA) of these mouse liver tumors and their relevance to humans was assessed based on the 2006 International Programme on Chemical Safety (IPCS) Human Relevance Framework. Epyrifenacil is not genotoxic and induced liver tumors via the postulated porphyria-mediated cytotoxicity MOA with the following key events: (#1) PPO inhibition; (#2) porphyrin accumulation; (#3) hepatocellular injury; with (#4) subsequent regenerative cell proliferation; and ultimately (#5) development of liver tumors. This article evaluates the weight of evidence for this MOA based on the modified Bradford Hill criteria. The MOA data were aligned with the dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a porphyria-mediated cytotoxicity MOA while excluding other alternative MOAs. Although the postulated MOA could qualitatively potentially occur in humans, we demonstrate that it is unlikely to occur in humans because of quantitative toxicodynamic and toxicokinetic differences between mice and humans. Therefore, this MOA is considered not relevant to humans, utilizing the IPCS Human Relevance Framework; consequently, a nonlinear, threshold dose response would be appropriate for human risk assessment.

Contribution of Toxicology in Sustainable Development

Contribution of Toxicology in Sustainable Development

Chloroacetanilide herbicide-induced rat enterochromaffin cell tumors: a case study within the context of the IPCS framework, for analyzing the relevance of a cancer mode of action for humans

The WHO International Programme on Chemical Safety (IPCS) framework for analyzing the relevance of a cancer mode of action (MoA) for humans (IPCS cancer-HRF) is an application to assess human relevance of tumorigenic hazards found through rodent bioassays. The chloroacetanilide herbicides, butachlor and alachlor, induced enterochromaffin-like (ECL) cell tumors in rat stomachs, at the highest doses. This study analyzed the human relevance of this tumor by applying the IPCS cancer-HRF using published data. In a postulated MoA, early key events (KEs) included decreased mucosal thickness in the fundic region, due to reduced parietal cells. The following KEs included increased pH of gastric acid and hypergastrinemia, leading to enhanced cell proliferation and hyperplasia, and resulting in the outcome of an ECL cell tumor. The data showed consistencies in dose-response and temporal concordance with the KEs and specificity in the tumor response, providing strengthened evidence of the KEs. While the early KE was not the same, similar MoAs have already been established for omeprazole and ciprofloxacin. The integrated data indicated that the postulated MoAs were biologically plausible. Alternative MoAs were excluded.. Based on sufficient evidence, an MoA was established in rats. When addressing chemically inducible MoAs of human relevance, KEs of hypergastrinemia and trophic ECL cell hyperplasia were judged to not be qualitatively and quantitatively plausible in humans. The MoA in rats is unlikely to be present in humans; however, the potential effects on parietal cells cannot be excluded. Thus, the IPCS cancer-HRF is very useful for assessing human relevance.

Clinical profile of patients presenting with inhalational organophosphorus poisoning in central India: a retrospective study

Background: World Health Organisation (WHO) report through International Programme on Chemical Safety (IPCS), poisoning is a significant global public health problem. According to WHO data, in 2012 an estimated 193,460 people died worldwide from unintentional poisoning. Intentional and unintentional pesticide poisoning has been acknowledged as a serious problem in many countries, including India, Limited literature available on clinical profile of organophosphorus poisoning cases, with this background present study was attempted. Objective of the study was to know the clinical presentation of OP poisoning cases admitted in tertiary care hospital.Methods: A retrospective record based observational study was conducted.Results: A total of 535 patients presented in the emergency department with the clinical features of OP poisoning. Mean age of the persons presenting in the emergency was 33.3±10.1 years. Nausea and vomiting is the most commoner symptom reported by 60.7% of patients followed by giddinesss (41.3%), loose motion (28.2%) and secretions (9.5%). Signs like abnormal pupil size, fasciculations and inability to neck holding were common with 23.55% 19.3% and 21.1% respectively. Statistical significance was found between Serum acetylcholine esterase level and outcome of patients (p<0.01). 96.1% received treatment less than half an hours. 18 patients required ventilator and among these 13 were died.Conclusions: Majority of the patients were of young age with males outnumbering females. Nausea and vomiting was the most common symptom reported by the patients while abnormal pupil size was the most common sign observed at the emergency department.

Polycyclic Aromatic Hydrocarbons in Foods: A Critical Review

Objective: Polycyclic aromatic hydrocarbons (PAHs) are well researched chemicals in foods that have been found to exhibit mutagenic and carcinogenic potentials. This study examined available literature on polycyclic aromatic hydrocarbons in foods, sources, effects and remediation. Methods: Available literature on polycyclic aromatic hydrocarbons in foods, sources, effects and remediation was critically reviewed. Results: The review showed that carcinogenicity of PAHs varies from the potent to moderately carcinogenic PAHs which include 3-methylcholanthrene, Benzo[a]pyrene, dibenz[a,h]anthracene, 5-methylchrysene, and dibenz[a,j]anthracene, whereas benzo[e]pyrene, dibenz[a,c]anthracene, chrysene, benzo[c]phenanthrene and fluoranthene are relatively weak or inactive carcinogens. Cooking processes have been found to be a major source of PAHs in foods. Although, PAHs can also be formed during curing and processing of raw food prior to cooking, several researchers in recent years have shown that the major dietary sources of PAHs are fish and meat especially where there is high consumption of meat cooked over an open flame. Several procedures and methods have been developed recently to assess and detect PAHs in foods and more recently, bio-monitoring procedures have also been developed to assess human exposure to PAHs. Numerous organizations such as the United States Environmental Protection Agency (U.S. EPA), the International Agency for Research on Cancer (IACR), the Scientific Committee on Food (SCF), the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the International Programme on Chemical Safety (IPCS), and the European Food Safety Authority (EFSA) have been involved in evaluating the occurrence and toxicity of PAHs. Conclusion: Conclusively, taking into consideration the sources of PAHs generation, adequate process and quality control of the processed foods could be a veritable mean to reduce PAHs ingestion in foods.

Determination of Formaldehyde in Tofu by Sequential Injection Analysis Using Acetoacetanilide as Hantzsch Reaction Reagent

Formaldehyde is a toxic and dangerous compound that is still often used freely by irresponsible traders or producers as food additives. At low concentrations, formaldehyde can cause eye, nose, throat and skin irritations. Exposure to large amounts of formaldehyde can cause severe pain, vomiting, coma, and even death. According to the International Program on Chemical Safety (IPCS), the threshold for formaldehyde in food that can still be tolerated in adult bodies is 1.5 mg to 14 mg per day while in a drinking water is 0.1 ppm. Determination of formaldehyde generally employ a titration method, which requires a large amount of sample and reagent, and long analysis time. This work aims to determine the formaldehyde in tofu commercially available in traditional markets of Malang City by Sequential Injection Analysis method using acetoacetanilide (AAA) at optimum conditions. Determination of formaldehyde is based on the Hantzsch reaction, which involves a cyclization between AAA and formaldehyde in the presence of ammonia so that it will produce a yellow dihydropyridine derivative product detected at a wavelength of 359 nm. The optimum condition for the formation of the reaction product occurred at an AAA concentration of 0.03 M, an ammonium acetate concentration of 1.5 M, a reaction time of 50 s and a flow rate of 75 µL/s. Excellent sensitivity and accuracy could be attributed to our developed formaldehyde detection method as the detection limit of 4.5 ppb and the recovery values of > 95 were achieved. Low reagent consumption, less waste production, and high throughput analysis are other advantages of our proposed method.

1-Formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP): A Potential Proximate Carcinogenic Metabolite of Pyrrolizidine Alkaloids.

Pyrrolizidine alkaloids (PAs) are phytochemicals present in more than 6000 plant species worldwide; about half of the PAs are hepatotoxic, genotoxic, and carcinogenic. Because of their wide exposure and carcinogenicity, the International Programme on Chemical Safety (IPCS) concluded that PAs are a threat to human health and safety. We recently determined that PA-induced liver tumor initiation is mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-DNA adducts and proposed that these DHP-DNA adducts are biomarkers of PA exposure and liver tumor initiation. To validate the generality of this metabolic activation pathway and DHP-DNA adducts as biomarkers, it is significant to identify reactive metabolites associated with this metabolic activation pathway. Segall et al. ( Segall et al. ( 1984 ) Drug Metab. Dispos. 12 , 68 - 71 ) previously reported that 1-formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP) is generated from the metabolism of senecionine by mouse liver microsomes. In the present study, we examined the metabolism of seven hepatocarcinogenic PAs (senecionine, intermedine, retrorsine, riddelliine, DHR, heliotrine, and senkirkine) and one noncarcinogenic PA (platyphylline) by human, rat, and mouse liver microsomes. 1-CHO-DHP was identified as a common metabolite from the metabolism of these hepatotoxic PAs, but not from platyphylline. Incubation of 1-CHO-DHP with HepG2 and A549 cells produced the same set of DHP-DNA adducts, which were identified by both LC/MS MRM mode and selected ion monitoring analyses through comparison to synthetic standards. In the incubation medium of 1-CHO-DHP treated HepG2 cells, both DHP and 7-cysteine-DHP were formed, which were capable of binding to cellular DNA to produce DHP-DNA adducts. These results suggest that 1-CHO-DHP is a proximate DNA metabolite of genotoxic and carcinogenic PAs.

Combined Effects of Dust and Dietary Exposure of Occupational Workers and Local Residents to Short- and Medium-Chain Chlorinated Paraffins in a Mega E-Waste Recycling Industrial Park in South China

Four types of dust samples and nine categories of locally produced staple foods were collected from a mega e-waste recycling industrial park and its surrounding regions, and simultaneously analyzed for short-chain and medium-chain chlorinated paraffins (CPs) to estimate dust and dietary exposure and their combined effects on occupational workers and local residents. All samples related to e-waste activities contained considerably high concentrations of CPs. The highest dust concentration was found in e-waste workshops. CPs were highly accumulated in local plant and animal origin foods, most markedly in fish, vegetables, and rice. The main contribution to CP intake under a median exposure scenario was from the diet, and vegetables, fish, and rice were the three largest dietary intake sources. Only the combined dust and food exposure from the present study has approached or even exceeded the highest tolerable daily intake (TDI) set up by the International Program on Chemical Safety (IPCS). However, due to lack of official threshold values for CP exposure on adverse human health, there are limitations on accurate risk assessment. Considering the presence of other exposure pathways, CPs' endocrine disrupter properties, as well as the multicomponent chemical "cocktails" effects, potential high risks from CP exposure may be posed to e-waste workers and local residents.

1‐Formyl‐7‐hydroxy‐6,7‐dihydro‐5H‐pyrrolizine (9‐CHO‐DHP) ‐ A Biologically Proximate Pyrrolic Metabolite of Carcinogenic Pyrrolizidine Alkaloids

Pyrrolizidine alkaloids (PAs) are phytochemical constituents of more than 6000 plant species worldwide; approximately half of the PAs are hepatotoxic, genotoxic, and carcinogenic. Because of their wide exposure and carcinogenicity, the International Programme on Chemical Safety (IPCS) concluded that PAs are a threat to human health and safety. We recently determined that the metabolic activation pathway of PA‐induced liver tumor initiation is mediated by a set of four (±)‐6,7‐dihydro‐7‐hydroxy‐1‐hydroxymethyl‐5H‐pyrrolizine (DHP)‐derived DNA adducts, and proposed that these DHP‐DNA adducts are potential biomarkers of PA exposure and liver tumor initiation. To validate the generality of this metabolic activation pathway and DHP‐DNA adducts as biomarkers, it is important to identify the spectrum of reactive metabolites associated with this metabolic activation pathway. Segall et al. (Drug Metab. Disposit., 12, 68–71, 1984) reported that 1‐formyl‐7‐hydroxy‐6,7‐dihydro‐5H‐pyrrolizine (9‐CHO‐DHP) is a metabolite formed from the mouse liver microsomal metabolism of senecionine. In this present study, we examined the metabolism of six hepatocarcinogenic PAs (riddelliine, senecionine, monocrotaline, senkirkine, intermedine, and heliotrine) and one non‐carcinogenic PA (platphylline) by human, rat, and mouse liver microsomes. 9‐CHO‐DHP was found as a common metabolite from the metabolism of the six hepatotoxic PAs, but not from platphylline. Incubation of 9‐CHO‐DHP in HepG2 cells and A549 cells resulted in the formation of the same set of DHP‐DNA adducts, as assessed by both LC/MS SRM mode and selected ion monitoring analyses through comparison to synthetic standards. In the incubation medium of HepG2 cells, both DHP and 7‐cysteine‐DHP were identified. These metabolites have previously shown to be capable of binding to cellular DNA to produce DHP‐DNA adducts. Thus, when incubated with HepG2 cells, 9‐CHO‐DHP was metabolized to the reactive metabolites DHP and 7‐cysteine‐DHP, metabolites associated with the DHP‐DNA adduct formation. These results indicate that 9‐CHO‐DHP is a DNA proximate metabolite of hepatotoxic PAs and further support the generality of this metabolic activation pathway mediated by the formation of these DHP‐DNA adducts. [This abstract is not an official U.S. Food and Drug Administration (FDA) guidance or policy statement. No offcial support or endorsement by the U.S. FDA is intended or should be inferred. The authors declare no competing financial interest.]Support or Funding InformationThis research was supported in part by appointment (X.H.) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Case examples of an evaluation of the human relevance of the pyrethroids/pyrethrins-induced liver tumours in rodents based on the mode of action.

Rodent carcinogenicity studies are useful for screening for human carcinogens but they are not perfect. Some modes of action (MOAs) lead to cancers in both experimental rodents and humans, but others that lead to cancers in rodents do not do so in humans. Therefore, analysing the MOAs by which chemicals produce tumours in rodents and determining the relevance of such tumour data for human risk are critical. Recently, experimental data were obtained as case examples of an evaluation of the human relevance of pyrethroid (metofluthrin and momfluorothrin)- and pyrethrins-induced liver tumours in rats based on MOA. The MOA analysis, based on the International Programme on Chemical Safety (IPCS) framework, concluded that experimental data strongly support that the postulated MOA for metofluthrin-, momfluorothrin- and pyrethrins-produced rat hepatocellular tumours is mediated by constitutive androstane receptor (CAR) activation. Since metofluthrin and momfluorothrin are close structural analogues, reproducible outcomes for both chemicals provide confidence in the MOA findings. Furthermore, cultured human hepatocyte studies and humanized chimeric mouse liver studies demonstrated species difference between human hepatocytes (refractory to the mitogenic effects of these compounds) and rat hepatocytes (sensitive to their mitogenic effects). These data strongly support the hypothesis that the CAR-mediated MOA for liver tumorigenesis is of low carcinogenic risk for humans. In this research, in addition to cultured human hepatocyte studies, the usefulness of the humanized chimeric liver mouse models was clearly demonstrated. These data substantially influenced decisions in regulatory toxicology. In this review I comprehensively discuss the human relevance of the CAR-mediated MOA for rodent liver tumorigenesis based on published information, including our recent molecular research on CAR-mediated MOA.

Biomonitoring Equivalents for interpretation of urinary iodine

Iodine is an essential nutrient whose deficiency or excess exposure can cause adverse health effects. The primary sources of iodine exposure in the general population are iodized salt, dairy products, bread and sea food. Urinary iodine concentrations (UIC) have been measured by Canadian Health Measures Survey (CHMS) and US National Health and Nutrition Examination Survey (NHANES). The Institute of Medicine (IOM), the US Agency for Toxic Substances and Disease Registry (ATSDR) and World Health Organization (WHO) have established exposure guidance values for nutrition (IOM Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), WHO Recommended Nutrient Intake (RNI)) and toxicity (IOM Tolerable Upper Intake Level (UL); ATSDR Minimal Risk Level (MRL), WHO International Programme on Chemical Safety (IPCS) Tolerable Daily Intake (TDI)). Using a urinary excretion fraction of 0.9, Biomonitoring Equivalents (BE) for the EAR, RDA, UL and MRL were derived for adults (60, 100, 730 and 450 μg/L, respectively) and children (50, 80, 580 and 360 μg/L, respectively). The population median UIC values from NHANES and CHMS for adults (140–181, 122–126 μg/L, respectively) and children (232, 189 μg/L, respectively) were above the criteria for assessing iodine nutrition, indicating that US and Canadian populations are likely to have adequate population iodine nutrition. The median UIC from NHANES and CHMS do not exceed BE values derived from exposure guidance values for toxicity.

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies.

Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. Toxicol. Sci. 128, 284-294.) reported MOA studies identifying the following key events: increased metabolism of fluensulfone by CYP2f2 in mouse lung Club cells, followed by local proliferation, finally leading to adenoma formation. Human lung microsomes were found not to metabolize fluensulfone. The Joint FAO/WHO Meeting on Pesticide Residues has reviewed the previous data and concluded that the MOA is plausible however some areas of uncertainty were identified. This publication provides additional data to address these. New cell proliferation studies in mice showed that the MOA is functionally independent of sex. A threshold of cell proliferation in Club cells correlating with the dose response for adenoma formation was shown. CYP2f2 knockout mice did not react to fluensulfone exposure with cell proliferation like wild-type mice, confirming the key role of this enzyme. The collective data for fluensulfone were evaluated according to the International Programme on Chemical Safety (IPCS) Mode of Action Framework which leads to the conclusion that the mouse-specific lung tumors after fluensulfone are not relevant to humans.

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.

BackgroundThe issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs.MethodsWe have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity.ResultsBuilding from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs.ConclusionsWhen using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0156-6) contains supplementary material, which is available to authorized users.

The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science

The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science

Case study illustrating the WHO IPCS guidance on characterization and application of physiologically based pharmacokinetic models in risk assessment

The World Health Organization (WHO) International Programme on Chemical Safety (IPCS) Guidance on Characterization and Application of Physiologically Based Pharmacokinetic Models in Risk Assessment (IPCS, 2010) describes key principles for risk assessors and model developers. In the WHO Guidance, a template for model documentation was developed and a case study included. Here the WHO Guidance, including the template, is summarized and an additional case study is presented to illustrate its application, based upon an existing risk assessment for 2-butoxyethanol (CAS NO. 111-76-2). The goal of the WHO Guidance and the current paper is to increase regulatory acceptance of complex biologically descriptive pharmacokinetic (or toxicokinetic) models, such as PBPK models, by facilitating communication and successful interaction between modelers and risk assessors.

International experience in addressing combined exposures: Increasing the efficiency of assessment

More efficient methodology for assessing the impact of combined exposures to multiple chemicals has been considered in a project of the World Health Organization (WHO) International Programme on Chemical Safety (IPCS).Recommendations regarding terminology and the status of development of the framework, its content, review and application are described. Evolving experience in its application is illustrated by example (polybrominated diphenyls) with special emphasis on the critical content of problem formulation, the role of predictive tools in grouping of chemicals for consideration and the importance of explicit delineation of relative uncertainty and sensitivity for tiered assessment.Priorities in increasing the efficiency of risk assessment not only for combined exposures, but more generally based on experience acquired in developing the framework and its application in case studies are identified and recommendations included.

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework

Species-specific lung tumors in the mouse are induced by a number of chemicals. The underlying cause appears to be a high metabolic activity of mouse lung, due to relatively high abundance of Clara cells in mice compared with humans and the mouse-specific cytochrome P450 isoform 2f2 in the Clara cells. The chemicals are activated to reactive intermediates, leading to local cytotoxicity or mitogenicity resulting in increased cell proliferation and tumors. Rats have lower metabolic activity than mice (already below the threshold needed to cause lung tumors upon lifetime exposure) and activity in humans is lower than in rats. The carcinogenic risk for human lung is low for this mode of action (MOA). Fluensulfone has shown an increased incidence of lung adenomas in mice, but not in rats, at high doses. Fluensulfone is not genotoxic. MOA studies were conducted investigating key events of the postulated MOA. Fluensulfone is extensively metabolized by mouse lung microsomes, whereas no metabolic activity is seen with human lung microsomes. Cyp 2f2 is a major contributor in fluensulfone’s metabolism and Cyp 2e1 is not involved. Furthermore, administration of fluensulfone to mice led to an early increase in Clara cell proliferation. The International Programme on Chemical Safety (IPCS) MOA and human relevance framework was used to evaluate the collective data on fluensulfone. We concluded that fluensulfone leads to species-specific mouse lung tumors and that these tumors are likely not relevant to human hazard or risk.

Toxicogenomics in non-mammalian species—Editorial

In October 2004, the Organisation for Economic Co-operation and Development (OECD) and the International Programme on Chemical Safety (IPCS) organized a workshop in Kyoto Japan to outline the fundamental aspects and future directions of the then emerging science of “Toxicogenomics.” The output of this three-day meeting was summarized in the Report of the OECD/IPCS workshop on Toxicogenomics (OECD Series on Testing and Assessment, Number 50, http://www.who.int/ipcs/methods/oecd_report.pdf). In essence, Toxicogenomics was defined as any study that investigates the response of a genome to hazardous substances by means of (1) genomic-scale mRNA expression analyses (Transcriptomics), (2) cell and tissue wide protein expression techniques (Proteomics), or (3) cell and tissue wide metabolite profiling (Metabolomics). These “omic” datasets typically require intricate in silico analyses (Bioinformatics) to integrate the results and by doing so provide insights into mechanistic toxicology and biomarkers of exposure.

Medical toxicology: Need for recognition as a subspecialty

Medical toxicology: Need for recognition as a subspecialty

Poison treatment centers in Iran

In Iran, almost all emergency departments and most of the intensive care units (ICUs) treat poisoning patients, but there are some hospitals that serve to poisoning cases in a specific manner and are equipped with antidotes. Likely, Tehran, Mashhad, and Isfahan Universities have perfect clinical poisoning treatment centers that are mainly used for the education of medical students and residents. In Tehran, LoghmanHakim hospital poison center is an absolutely well-known and the most famous center for treatment of poisoning patients in Tehran and nearby cities. It is a teaching hospital affiliated to Shahid Beheshti University of Medical Sciences. Within this poison center, there is a perfect emergency department, unique intensive care unit (ICU) with 20 inpatient beds, and a specific poisoning ward. Also, the center has been joined by a Toxicological Research Center (TRC) that is located within the same hospital. Totally, there are 82 inpatient beds for intoxicated patients. Annually, more than 25,000 poisoned patients are referred to this center. The next famous poison center of Iran is Imam Reza hospital poison center, which is a treatment center for poisoning patients located in the city Mashhad. This center is affiliated to a teaching hospital owned by Mashhad University of Medical Sciences. This center has been joined to the Medical Toxicology Research Center (MTC), which has research labs, clinic, and ward for the poisoning patients. This center collaborates with the International Program on Chemical Safety (IPCS). The other active poisoning treatment center is the Emergency Department of Noor teaching hospital, located in Isfahan University of Medical Sciences in Isfahan. It consists of 6 ICU beds and 15 ward beds. Regularly, anesthesiology residents, interns, and other medical students are taught about management of poisoning cases in this center. The Clinical Toxicology Research Center, which is also located inside the Noor hospital, collaborates with this poison center in providing research projects to study on acute and chronic poisonings. Baharloo hospital is another teaching hospital affiliated to Tehran University of Medical Sciences, which has been newly established and has a perfect poisoning treatment center. This center has a 10-bed toxicology ICU and 15 ward beds to provide highly specialized care of various intoxications. Yaftabad hospital is another teaching hospital affiliated to Iran University of Medical Sciences located in Tehran, which has a separate emergency department for poisoned patients, equipped with 8-bed toxicology ICU. Razi hospital is another teaching hospital affiliated to Ahwaz Jundishapur University of Medical Sciences located in Ahwaz, a city in south of Iran. Razi hospital primarily focuses on toxicology of scorpion and snakes that are common in that region of the country. Shoshtari hospital is another teaching hospital affiliated to Shiraz University of Medical Sciences located in Shiraz. This hospital also has a specific 15-bed poisoning ward. Furthermore, there are other centers located in other cities including Arak, Ardabil, Birjand, Hamadan, Tabriz, Sari, Rasht, and Urmia, which have separate beds for management of poisoning cases; although they do not have special poisoning ward, they are improving. In addition, there are strong Drug and Poison Information Centers (DPICs) that work under the supervision of the Medical Universities and the Food and Drug Department of the Ministry of Health (MOH). The first official DPIC was established in 1995 at Tehran by a team supervised by Prof Mohammad