Risk Assessment of Polycyclic Aromatic Hydrocarbons and Heterocyclic Aromatic Amines in Processed Meat, Cooked Meat and Fish-Based Products Using the Margin of Exposure Approach.

Background: The objective of this study is to assess the risk of exposure of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) in meat and fish-based products marketed in Malaysia using the margin of exposure (MOE) approach. Methods: Benchmark Dose (BMD) software was used to model the BMD at a lower end of a one-sided 95% confidence interval with a 10% incremental risk (BMDL10) of PAHs and HCAs from different target organ toxicities. The MOEs of PAHs and HCAs in meat and fish-based products were determined by utilising the calculated BMDL10 values and estimated daily intake of meat and fish-based products from published data. Results: The calculated BMDL10 values of PAHs (i.e. benzo[a]pyrene [BaP] and fluoranthene [FA]) and HCAs (i.e. 2-amino-3,8,dimethylimidazo[4,5-f]quinoxaline [MeIQx] and 2-amino-1-methyl-6-phenylimidazo[4,5,6]pyridine [PhIP]) ranged from 19 mg/kg bw/day to 71,801 mg/kg bw/day. The MOE of BaP ranged from 41,895 to 71,801 and that of FA ranged from 19 to 1412. As for MeIQx and PhIP, their MOEs ranged from 6,322 to 7,652 and from 2,362 to 14,390, respectively. Conclusion: The MOEs of FA, MeIQx and PhIP were lower than 10,000, indicating a high concern for human health and therefore demanding effective risk management actions.

The Malaysian Society of Toxicology: from establishment to evolution, a promising future!

The Malaysian Society of Toxicology (MySOT), founded in 2010, emerged as a response to the growing need for a collective and interdisciplinary effort to study the effects of substances on human health, and the environment. By fostering collaboration between toxicologists, researchers, regulators, industry experts, and various relevant subject matter experts, MySOT has played a vital role in generating knowledge and promoting safety to safeguard both human and environmental well-being. Within the 13 years since its establishment, MySOT has made substantial progress in the advancement of toxicology in Malaysia. Over the years, MySOT has supported many initiatives, including organizing conferences, seminars, and workshops in which experts from various fields present their research, discuss emerging trends, and propose strategies to reduce toxic substance exposure risk. The society has also been actively involved in the broader landscape of toxicology research and policy influence in Malaysia. MySOT shoulders the responsibility of conveying accurate information and educating the public about health risks associated with toxic substances. Therefore, the society aims to collaborate with governmental organizations, professional bodies, and international toxicology organizations to share ideas, resources, and expertise. MySOT seeks to gather toxicological experts in the region and significantly contribute to a safer and healthier community, therefore supporting the United Nations Sustainable Development Goals (SDGs), by being actively involved with all of its stakeholders, both local and international.

Risk assessment of aflatoxin B1 in herbal medicines and plant food supplements marketed in Malaysia using margin of exposure and RISK21 approaches.

Aflatoxin B1 (AFB1) is a mycotoxin produced by several species of Aspergillus fungi which can cause liver cancer in animals and humans. This study aims to perform the risk assessment of AFB1 in herbal medicines and plant food supplements (PFS) in Malaysian market. A total of 31 herbal medicines and PFS were purchased through online platforms and over the counter using a targeted sampling strategy. Of 31 samples analysed using the ELISA method, 25 (80.6%) were contaminated with AFB1 at levels ranged from 0.275 to 13.941 µg/kg. The Benchmark Dose Lower Confidence level of 10 (BMDL10) of 63.46 ng/kg bw/day and the estimated dietary intake of the adult population ranged from 0.006 to 10.456 ng/kg bw/day were used to calculate the Margin of Exposure (MOE). The MOEs for 24 (96%) out of the 25 positive samples were lower than 10,000. The RISK21 matrix revealed that AFB1 exposure levels from herbal medicines and PFS differed greatly over the world. The calculated population risk of acquiring liver cancer from AFB1 exposure ranged from 0 to 0.261 cancers/100,000 populations/year and accounted for an estimated percentage of liver cancer incidence ranged from 0.002 to 4.149%. This study revealed a moderate risk of liver cancer attributable to AFB1 from herbal medicine and PFS among Malaysian populations and emphasised an urgency for risk management actions.

Safety assessment of natural products in Malaysia: current practices, challenges, and new strategies.

The belief that natural products are inherently safe is a primary reason for consumers to choose traditional medicines and herbal supplements for health maintenance and disease prevention. Unfortunately, some natural products on the market have been found to contain toxic compounds, such as heavy metals and microbes, as well as banned ingredients such as aristolochic acids. It shows that the existing regulatory system is inadequate and highlights the importance of thorough safety evaluations. In Malaysia, the National Pharmaceutical Regulatory Agency is responsible for the regulatory control of medicinal products and cosmetics, including natural products. For registration purpose, the safety of natural products is primarily determined through the review of documents, including monographs, research articles and scientific reports. One of the main factors hampering safety evaluations of natural products is the lack of toxicological data from animal studies. However, international regulatory agencies such as the European Food Safety Authority and the United States Food and Drug Administration are beginning to accept data obtained using alternative strategies such as non-animal predictive toxicological tools. Our paper discusses the use of state-of-the-art techniques, including chemometrics, in silico modelling and omics technologies and their applications to the safety assessments of natural products.

Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach.

Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing.

Malaysia: country report on children's environmental health.

Children's environmental health (CEH) has become a main agenda in the National Environmental Health Action Plan (NEHAP) 2019 in Malaysia. Children are affected by exposure to many environmental hazards because they are uniquely vulnerable due to their immature immune systems and organs. This country report aims to review the environmental threats to CEH in Malaysia. There are a few key issues that have been identified, including air pollution, pesticides in food and water pollution. However, air pollution has been recognized as one of the major concerns in CEH, coming from both localized and transboundary sources. The localized sources include traffic-related air pollutants, industrial waste incinerators, land clearing and open burning. In addition, due to the tropical climate, children are exposed to fungal toxins, mycotoxins, endotoxins and allergens from classroom dust. Transboundary pollutants from neighboring countries result in recurring haze episodes in Malaysia, causing a negative impact on public health, especially in children. All in all, improving CEH in Malaysia requires all stakeholders and related agencies to recognize the issue as a problem, to develop a harmonized action plan and to work together to promote the protection of human health, specifically of children.

Mutagenic Study of Benzimidazole Derivatives with (+S9) and without (-S9) Metabolic Activation.

Benzimidazole derivatives have a diverse range of biological activities, including antiulcer, antihypertensive, antiviral, antifungal, anti-inflammatory, and anticancer. Despite these activities, previous studies have revealed that some of the derivatives can induce mutations. This study aimed to screen for potential mutagenic activities of novel benzimidazole derivatives 1-4 using the Ames test and to study their structure-activity relationship (SAR). An Ames test was carried out on two strains of Salmonella typhimurium (TA98 and TA100) in the absence and presence of metabolic activation. Genetic analysis was performed prior to the Ames test to determine the genotypes of the bacterial tester strains. Both bacterial strains showed dependency on histidine with the presence of rfa mutation, uvrB deletion, and plasmid pKM101. Further, all derivatives tested showed no mutagenic activity in the absence of metabolic activation in both tester strains. However, in the presence of metabolic activation, compound 1 appeared to induce mutation at 2.5 µg/plate when tested against the TA98 strain. These results suggest that the absence of the -OH group at the ortho-position over the phenyl ring might be the cause of increased mutagenic activity in compound 1. Additionally, the presence of mutagenic activity in compound 1 when it was metabolically activated indicates that this compound is a promutagen.

Recent updates on phthalate exposure and human health: a special focus on liver toxicity and stem cell regeneration.

Phthalates have been blended in various compositions as plasticizers worldwide for a variety of purposes. Consequently, humans are exposed to a wide spectrum of phthalates that needs to be researched and understood correctly. The goal of this review is to focus on phthalate's internal exposure pathways and possible role of human digestion on liver toxicity. In addition, special focus was made on stem cell therapy in reverting liver toxicity. The known entry of higher molecular weight phthalates is through ingestion while inhalation and dermal pathways are for lower molecular weight phthalates. In human body, certain phthalates are digested through phase 1 (hydrolysis, oxidation) and phase 2 (conjugation) metabolic processes. The phthalates that are made bioavailable through digestion enter the blood stream and reach the liver for further detoxification, and these are excreted via urine and/or feces. Bis(2-ethylhexyl) phthalate (DEHP) is a compound well studied involving human metabolism. Liver plays a pivotal role in humans for detoxification of pollutants. Thus, continuous exposure to phthalates in humans may lead to inhibition of liver detoxifying enzymes and may result in liver dysfunction. The potential of stem cell therapy addressed herewith will revert liver dysfunction and lead to restoration of liver function properly.

Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach.

After the incidences of induction of aristolochic acid nephropathy after consumption of herbal weight loss preparations that accidentally contained aristolochic acids (AAs), several countries defined national restrictions on the presence of AAs in food, including plant food supplements (PFS) and herbal products. This study investigates whether the risks associated with exposure to AAs via PFS and herbal products are at present indeed negligible. Data reported in literature on AA levels in PFS and other herbal products and also obtained from a new series of PFS in the present study were used to calculate the estimated daily intakes (EDIs) and corresponding margins of exposure (MOEs). Available literature data revealed that 206 out of 573 samples were found to contain aristolochic acid I (AAI) and/or aristolochic acid II (AAII). The results obtained from recently collected PFS revealed that both AAI and AAII were detected in three out of 18 analysed PFS at levels up to 594.8 and 235.3 µg g-1, respectively, being in line with the levels reported in literature. The EDIs resulting from intake of these PFS resulted in MOEs that were generally below 10,000, corroborating the priority for risk management. Although these results refer to PFS collected by targeted sampling strategies, the data reveal that AA-containing PFS are still freely available. When considering that the use of these samples may be limited to shorter periods of time, the EDIs might be lower, but MOE values would still be lower than 10,000 for more than 50% of the AA-containing PFS and herbal products. In conclusion, the presence of AAs in PFS and herbal products even several years after instalment of the legal restrictions still raises concern, especially for people who frequently use the respective PFS and herbal products.

Predicting points of departure for risk assessment based on in vitro cytotoxicity data and physiologically based kinetic (PBK) modeling: The case of kidney toxicity induced by aristolochic acid I.

Aristolochic acids are naturally occurring nephrotoxins. This study aims to investigate whether physiologically based kinetic (PBK) model-based reverse dosimetry could convert in vitro concentration-response curves of aristolochic acid I (AAI) to in vivo dose response-curves for nephrotoxicity in rat, mouse and human. To achieve this extrapolation, PBK models were developed for AAI in these different species. Subsequently, concentration-response curves obtained from in vitro cytotoxicity models were translated to in vivo dose-response curves using PBK model-based reverse dosimetry. From the predicted in vivo dose-response curves, points of departure (PODs) for risk assessment could be derived. The PBK models elucidated species differences in the kinetics of AAI with the overall catalytic efficiency for metabolic conversion of AAI to aristolochic acid Ia (AAIa) being 2-fold higher for rat and 64-fold higher for mouse than human. Results show that the predicted PODs generally fall within the range of PODs derived from the available in vivo studies. This study provides proof of principle for a new method to predict a POD for in vivo nephrotoxicity by integrating in vitro toxicity testing with in silico PBK model-based reverse dosimetry.

Study of heavy metal levels among farmers of Muda Agricultural Development Authority, Malaysia.

Heavy metals, particularly cadmium, lead, and arsenic, constitute a significant potential threat to human health. This study was conducted to determine the levels of cadmium, lead, and arsenic in nail samples from farmers at Muda Agricultural Development Authority (MADA), Kedah, Malaysia, and evaluate factors that can contribute to their accumulations. A total of 116 farmers participated in this study. Inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze concentration of heavy metals in the nail samples and questionnaires were given to participants to get demographic, health status, and their agricultural activities data. In this paper, the level of heavy metals was within the normal range and varies according to demographic factors. We found that there were significant correlations between working period with level of lead and arsenic (r=0.315 and r=0.242, resp., P<0.01) and age with lead level (r=0.175, P<0.05). Our findings suggested that agricultural activities could contribute to the accumulation of heavy metals in farmers. Hence, the control of environmental levels of and human exposure to these metals to prevent adverse health effects is still an important public health issue.