A refined approach to estimate exposure for use in calculating the Maximum Residue Limit of veterinary drugs

Maximum Residue Limits (MRLs) are standards that represent the maximum residue concentration expected to be found if a veterinary drug is administered according to good practice in the use of veterinary drugs (GVP). MRLs are established only where the exposure to residues in food resulting from particular use patterns of the veterinary drug pass a public health risk assessment. The current model diet as used by major regulators overstates mean consumption of food for populations when compared to results from food surveys of actual consumption. Exposure to residues is overestimated when calculating long-term (chronic) exposure using the model diet leading to the risk to consumers being overstated. Additionally the model diet underestimates the size of large portions eaten by the group of consumers that eat large quantities of a particular food in a single meal potentially leading to understating of risks associated with exposure to residues of drugs that produce an adverse effect after a single exposure. A revision of dietary consumption figures is proposed that will better match the consumption figures used in point-estimates of dietary exposure to the timeframe for consumption that is relevant to the reference dose.     

Codex Committee on Pesticide Residues--a plan for improved participation by governments.

The Codex Committee on Pesticide Residues (CCPR), which is responsible for establishing maximum residue limits (MRLs) for pesticides on food, has a vital role in protecting the public health and facilitating international trade. Codex MRLs are based on scientific evaluations by expert panels that constitute the Joint FAO/WHO Meeting on Pesticide Residues (JMPR). These panelists estimate an acceptable daily intake for a pesticide and expected level of residue remaining in food when the pesticide is used according to good agricultural practice. The goals of the CCPR are not being fully achieved. Governments are generally not accepting Codex MRLs; instead, technical and procedural aspects of the JMPR and CCPR process are being criticized. The CCPR is responding to valid criticisms of the process; however, governments may still lack the will to seek harmonization of pesticide limits for food in international trade. Overcoming this problem will be difficult, but not impossible. A plan of action is proposed that allows countries to selectively accept Codex MRLs, increase the number of chemicals in the JMPR/CCPR system for evaluation, and be responsive to both their consumers and their food producers without compromising national health and safety standards and competitive trade advantages.     

A simple procedure for estimating pseudo risk ratios from exposure to non-carcinogenic chemical mixtures

Non-cancer risk assessment traditionally assumes a threshold of effect, below which there is a negligible risk of an adverse effect. The Agency for Toxic Substances and Disease Registry derives health-based guidance values known as Minimal Risk Levels (MRLs) as estimates of the toxicity threshold for non-carcinogens. Although the definition of an MRL, as well as EPA reference dose values (RfD and RfC), is a level that corresponds to “negligible risk,” they represent daily exposure doses or concentrations, not risks. We present a new approach to calculate the risk at exposure to specific doses for chemical mixtures, the assumption in this approach is to assign de minimis risk at the MRL. The assigned risk enables the estimation of parameters in an exponential model, providing a complete dose–response curve for each compound from the chosen point of departure to zero. We estimated parameters for 27 chemicals. The value of k, which determines the shape of the dose–response curve, was moderately insensitive to the choice of the risk at the MRL. The approach presented here allows for the calculation of a risk from a single substance or the combined risk from multiple chemical exposures in a community. The methodology is applicable from point of departure data derived from quantal data, such as data from benchmark dose analyses or from data that can be transformed into probabilities, such as lowest-observed-adverse-effect level. The individual risks are used to calculate risk ratios that can facilitate comparison and cost-benefit analyses of environmental contamination control strategies.     

The Role of the World Health Organization in the Evaluation of Pesticides

The International Programme on Chemical Safety (IPCS), which is a cooperative program of the World Health Organization (WHO). United Nations Environment Programme (UNEP), and International Labour Organisation (ILO), directs a number of pesticide activities, including the WHO component of the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) and the preparation of Environmental Health Criteria (EHC) documents and Health and Safety Guides (HSGs) on pesticides. The intake of pesticide residues is being predicted at the international level, which is based upon the maximum residue limits (MRLs) that are estimated by JMPR. Acceptance of the MRLs is increased when the prediction does not exceed the acceptable daily intake (ADI). IPCS is active in developing new methodologies and in developing scientific consensus documents on the assessment of health risks from exposure to chemicals. Two new initiatives are a project to obtain agreement among important national institutions on the approaches to be taken for the interpretation of data relating to specific effects and the development of a "Joint Meeting on Pesticides," which will provide comprehensive reviews of pesticide safety and use.     

Problems of positive list system revealed by survey of pesticide residue in food

The positive list system became effective from May 29, 2006 to improve the regulation of residual agricultural chemicals (pesticides, feed additives and veterinary drugs) in foods. In accordance with the system, we investigated pesticide residues in 50 agricultural products purchased in Morioka city from March to November 2006. Analyses were performed according to the "Multiresidue Method for Agricultural Chemicals by GC/MS", the Notice of the Ministry of Health, Labour and Welfare. Five pesticides and two non-agricultural chemicals were detected from 16 samples. Ortho-phenylphenol (OPP) was detected from 8 samples: immature pea, snap bean, kiwi, plain-boiled bamboo shoot, mango, white asparagus, lemon and domestic shiitake mushroom. Maximum residue limits (MRLs) have not been established for these products, and they exceeded the uniform level of 0.01 ppm. DDT was detected from Philippines banana (0.30 ppm) and Korean paprika (0.45 ppm). The residual level in Philippines banana was lower than the MRL, but Korean paprika exceeded its MRL. Chlorpyrifos, Thiabendazole and Imazaril were detected from citrus imported from the U.S.A., but their residue levels were lower than the respective MRLs. Aniline and 2-pyrrolidone were detected from several imported products. These two may not be regulated by the positive list system because they are not agricultural chemicals, although their derivatives are used as pesticides or veterinary drugs. Three problems have been revealed from this survey: 1) application of the uniform level to minor agricultural products, 2) residues of non-agricultural chemicals whose toxicity is uncertain, 3) metabolites of agricultural chemicals, which are also regulated by the positive list system, have not been clearly defined.     

Evaluation of FAO/WHO pesticide standards in relation to polish and honduran diets

The FAO/WHO Codex Alimentarius Commission publishes a Guide to Codex Maximum Limits for Pesticide Residues (1978) which gives both acceptable daily intake (ADI) values and maximum residue limit (MRL) values for many pesticides in raw agricultural commodities (rac's) from crops on which their use is approved. ADI values are determined from animal toxicology data which give a no-observable-effect level (NOEL) and use of a safety factor. Specific MRL values are calculated from the ADI and a food factor (F), which is the decimal fraction of that rac in the assumed typical diet. One of the difficulties with this procedure is that dietary patterns differ substantially between countries. Whatever dietary pattern is assumed in calculation of the MRLs may be inappropriate for that country. Theoretical maximum residue intakes (TMRIs) were calculated from the Codex ADIs and MRLs using F values calculated from the national dietary patterns published separately in Poland and Honduras. The equation is TMRI = ΣMRL_i × F_i × D, where D is the daily individual diet weight of rac's in kilograms for the particular country. The TMRI should be lower than the maximum permitted intake (MPI) calculated as MPI = ADI × 60, where the 60 is an arbitrary human body weight in kilograms. The TMRI exceeded the MPI for 16 of 33 pesticides used in Poland and for 10 of 20 used in Honduras. At the extreme, the Polish TMRI/MPI ratio for aldrin-dieldrin is 19.5 and 18.1 for fenithion; nine pesticides had ratios of 4.0 or higher. For Honduras, piperonyl butoxide gave the highest ratio, 5.7 and three pesticides had ratios of 4.0 or higher. For Poland, the MRLs for 13 pesticides would cause the MPI to be exceeded by the theoretical residue concentrations of only one crop; in Honduras, seven pesticides have single-crop TMRIs greater than the MPI. Thus, these standards appear inappropriate for Poland and Honduras.     

Public Health Guidance Values for Chemical Mixtures: Current Practice and Future Directions

Agency for Toxic Substances and Disease Registry (ATSDR) utilizes chemical-specific minimal risk levels (MRLs) to assist in evaluating public health risks associated with exposure to hazardous substances. The MRLs are derived based on the data compiled from current worldwide literature searches and presented in ATSDR's toxicological profiles. These documents profile not only individual chemicals, but also groups of chemically related compounds and chemical mixtures. ATSDR took several approaches when developing MRLs for chemical mixtures. In some instances, toxicity equivalency factors were used to estimate the toxicity of the whole mixture; in other instances, the most toxic chemical was assumed to drive the health assessment for the whole mixture. Another approach was to treat the mixture as one entity and develop a health guidance value for the whole mixture. In yet another approach, each chemical of the mixture was evaluated separately and several health guidance values were developed. In the future, ATSDR will evaluate priority chemical mixtures found at hazardous waste sites. A weight-of-evidence approach, physiologically based pharmacokinetic modeling and benchmark dose modeling, and quantitative structure–activity relationships will have an impact on the development of MRLs and the assessment of chemical mixtures.     

Health effects classification and its role in the derivation of minimal risk levels: hepatic effects

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health based guidance values called minimal risk levels (MRLs) to assist with assessment of risks posed by exposures to hazardous chemicals. Current MRLs are posted on ATSDR's web site (www.atsdr.cdc.gov). From the total 326 MRLs currently posted, 79 MRLs are based on hepatic endpoints. The paper reports on endpoints used for the derivation of these MRLs and the use of uncertainty factors. It also describes the ranking of effects into less serious and serious categories as described in ATSDR's Guidance for Developing Toxicological Profiles.     

基于点评估方法的人参中农药残留摄入暴露风险研究

目的：了解2015年版《中国药典》执行后市场人参有机氯的合格情况,研究标准限度的适用性;同时进一步探索点评估方式在中药农药残留暴露评估中的应用。方法：采用《中国药典》2015年版四部有机氯法对86批人参中17种有机氯农药进行测定;采用点评估模式,计算急性和慢性摄入风险;同时采用慢性风险的消费者保护水平（CPL_c）来评价现行药典人参农残最大残留限量（MRL）标准对消费者的保护水平。结果：86批样品中合格样品为38批,合格率为44.2%,不合格样品集中为五氯硝基苯（PCNB）超标,其超标率达到55.8%。通过点评估法得出,除PCNB的急性风险商超过100%外,其余农药的急性、慢性风险商均远低于100%,说明风险较小。PCNB和六六六MRL值对消费者慢性摄入风险的保护水平分别为6.9倍和2.5倍,可认为目前PCNB和六六六的MRL标准有效地保护了消费者的膳食健康。结论：本研究探索点评估模式在人参有机氯农药残留暴露评估中的应用,并利用科学评估结果对标准限量的适用性、合理性提出相关建议。     

Health effects classification and its role in the derivation of minimal risk levels: reproductive and endocrine effects

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health-based guidance values called minimal risk levels (MRLs) to assist with assessment of risks posed by exposures to hazardous chemicals. From the total of 326 MRLs currently posted on ATSDR's web site (www.atsdr.cdc.gov), 14 and 5 MRLs are based on reproductive and endocrine endpoints, respectively. The paper also describes the ranking of effects into less serious and serious categories according to ATSDR's Guidance for Developing Toxicological Profiles, endpoints used for the MRLs derivation, and the use of uncertainty factors.     

Organochlorine pesticide residues in wheat from Konya region,Turkey

The present study has been carried out to evaluate the organochlorine pesticide contamination in wheat from Konya region. This region is the largest area of cereal production in Turkey. The contamination level has been determined according to the European Community Directives. Different wheat samples (36) were obtained from local farmers and wheat factories in this region. All the wheat samples examined were found to be contaminated by organochlorine pesticide residues of cis-Chlordane and methoxychlor. Chlordane isomers, methoxychlor, DDT and its metabolites, aldrin, β HCH, heptachlor and lindane have been found to be the highest organochlorine pesticide residues. In some of these samples, various organochlorine pesticide residues have been determined to be higher than European Community maximum residual limits. The residues of aldrin in one sample, trans-Chlordane in one sample, oxy-chlordane in eight samples and methoxychlor in one sample were found to be in excess of EC MRLs. Since most of the samples have been found to be contaminated with residues and some residues exceed EC MRLs, a control of organochlorine pesticide residues in wheat is necessary.     

Residues and dissipation kinetics of carbendazim and diethofencarb in tomato (Lycopersicon esculentum Mill.) and intake risk assessment

Dissipation behaviors and residues of carbendazim and diethofencarb in combination in tomato were investigated. The half-lives were 2.1–3.4 days for carbendazim, and 1.8–3.2 days for diethofencarb at a dose of 1.5 times of the recommended dosage. The residues of carbendazim and diethofencarb were below the maximum residue limits (MRLs) in China one day after application of the combination. The ultimate residues were significantly lower than the maximum permissible intake (MPI) in China at the recommended high dose for both child and adult. The values of the maximum dietary exposure for carbendazim and diethofencarb were 0.26 and 0.27 mg per person per day, respectively. The theoretical maximum daily intake (TMDI) values for carbendazim and diethofencarb were 1.5 and 0.5 mg/day, respectively. The dietary exposure was lower than the MPI, which indicates the harvested tomato samples under the experimental conditions (open field) are safe for human consumption at the recommended high dosage of the wettable powder.     

Hazard assessment using an in-silico toxicity assessment of the transformation products of boscalid,pyraclostrobin, fenbuconazole and glyphosate generated by exposure to an advanced oxidative process

Agricultural pesticide use is ongoing and consumer concern regarding the safety of pesticide residues on produce has generated interest in techniques that can safely reduce residues post-harvest. Recently an advanced oxidative process has shown promise in substantial residue reduction on the surface of produce. Given the potential for oxidative transformation of pesticides to generate transformation products with greater toxicity than the parent residue, take for example the oxon products of the organophosphorus insecticides, it is important to consider what transformation products are generated by pesticide exposure to an oxidative process and their potential toxicity. In this study, previously published transformation products of boscalid, pyraclostrobin, fenbuconazole and glyphosate were identified after exposure to 3% hydrogen peroxide, UV-C irradiation or their combination in an advanced oxidative process on glass, their oral toxicity, carcinogenicity and developmental toxicity were identified in-silico and an initial tier hazard assessment was conducted. Of the 87 total structures that were searched for, 53 were detected by UPLC-QTOF-MS and identified by mass spectra: 15, 13, 22 and 3 structures for boscalid, pyraclostrobin, fenbuconazole and glyphosate respectively, including the parent residues. Oral toxicity of the transformation products of pyraclostrobin and glyphosate was similar to or lower than the parent residue. Several transformation products of boscalid and fenbuconazole were estimated to be significantly more orally toxic than their parent residues. While the majority of the transformation products of boscalid, pyraclostrobin and fenbuconazole were predicted to be carcinogenic there were 11 that were consistently identified to have carcinogenic potential by several assessments. 29 of the 53 molecules were predicted to be probable developmental toxicants. An initial tier hazard assessment was conducted for Cramer rules classification and mutagenicity using the threshold of toxicological concern approach and predicted rat oral LD₅₀. Two exposure scenarios were considered, one highly protective considering each transformation product to be at the highest maximum residue limit (MRL) for the pesticide and whole produce consumption at the highest consumption rate from the USEPA Exposures Handbook, the other considering only apple consumption with the relevant MRL. As indicated by the hazard assessment, several transformation products of boscalid, pyraclostrobin and fenbuconazole should be strongly considered for further testing, either by quantifying their production or in-vivo and in-vitro toxicity tests due to their predicted toxicity and associated hazard.     

Relevance of integrating agricultural practices in pesticide dietary intake indicator

The aim of this study is to develop a new indicator of pesticide dietary intake to screen pesticides to include in monitoring programs. This new indicator called the adjusted TMDI (TMDI_Ad), taking account actual pesticide agricultural uses in France, is more precise than the theoretical maximum dietary intake (TMDI), based on maximum residue levels (MRLs) that is usually used.     

Capillary electrophoresis in analysis of veterinary drugs

Antibiotics are extensively applied in veterinary medicine for the treatment of various bacterial infections. Because of their use in food producing animals, the risk of occurrence of unwanted residues in edible products exists. To ensure human food safety, The European Union has defined maximum residue limits (MRLs) for veterinary drug residues in food products. Analytical methods need to be developed to confirm the presence of antibiotics at the MRL level. A capillary electrophoresis (CE) method with UV detection is proposed for the quantitative determination of residues from poultry and porcine tissues. Eight of the most frequently used antibiotics and nifursol, which routinely used as poultry coccidiostat, were analysed. CE technique permitted analysing substances to be separated from muscle, liver, kidney and skin with fat after a simple extraction with acetonitrile or ethyl acetate under basic conditions. Proposed method is capable to identify drug residues in tissues at level below 20 microg/kg.     

采用相对效能因子法对枸杞中拟除虫菊酯类农药的慢性累积暴露评估

目的：对枸杞中拟除虫菊酯类农药残留带来的累积暴露量进行评估,并探讨相对效能因子法 (RPF)在中药中农药残留累积风险评估中的应用。方法：采用GC-MS/MS法对40批枸杞药材中15种拟除虫菊酯类农药进行检测分析。以溴氰菊酯作为指示农药,采用RPF法,计算拟除虫菊酯类农药的累积暴露量,并与每日允许摄入量(ADI)进行比较,分析风险。同时采用危害指数法(HI)评价累积风险,并对两种方法进行比较。结果：40批枸杞样品中共有4种拟除虫菊酯类农药检出,样品检出率为 84.5%,其中有67.6%的样品中检出2种及以上拟除虫菊酯类农药。通过RPF法和HI法计算得累积风险值分别为0.000205和0.000218,均远低于1,表明累积摄入风险较低。同时发现通过2种方法得出的风险评价一致,但不同方法中各农药的风险贡献值有较大差异,这与2种方法所选择的毒性判断终点不同有关。 结论：通过摄入枸杞中拟除虫菊酯类农药对人体产生的健康风险尚处于可接受水平,并且首次探索了 RPF法在中药农药残留累积评估中的应用,为逐步完善中药中农药残留风险评估系统提供了借鉴。     

Cumulative dietary exposure to a selected group of pesticides of the triazole group in different European countries according to the EFSA guidance on probabilistic modelling

The practicality was examined of performing a cumulative dietary exposure assessment according to the requirements of the EFSA guidance on probabilistic modelling. For this the acute and chronic cumulative exposure to triazole pesticides was estimated using national food consumption and monitoring data of eight European countries. Both the acute and chronic cumulative dietary exposures were calculated according to two model runs (optimistic and pessimistic) as recommended in the EFSA guidance. The exposures obtained with these model runs differed substantially for all countries, with the highest exposures obtained with the pessimistic model run. In this model run, animal commodities including cattle milk and different meat types, entered in the exposure calculations at the level of the maximum residue limit (MRL), contributed most to the exposure. We conclude that application of the optimistic model run on a routine basis for cumulative assessments is feasible. The pessimistic model run is laborious and the exposure results could be too far from reality. More experience with this approach is needed to stimulate the discussion of the feasibility of all the requirements, especially the inclusion of MRLs of animal commodities which seem to result in unrealistic conclusions regarding their contribution to the dietary exposure.     

Health effects classification and its role in the derivation of minimal risk levels: renal effects

The Agency for Toxic Substances and Disease Registry (ATSDR) derives minimal risk levels (MRLs) for priority hazardous substances. MRLs are health guidance values intended to serve as screening levels for health assessors to select contaminants of concern and to assess potential health effects at hazardous waste sites and areas affected by unplanned releases. Current MRLs are published in ATSDR toxicological profiles and are listed at the ATSDR website at . To date, ATSDR has derived 125 inhalation MRLs, 207 oral MRLs, and eight external radiation MRLs; 19 MRLs are based on renal effects. This article reports on endpoints used to derive the MRLs. It also presents the ranking of effects into less serious and serious categories as described in ATSDR's Guidance for Developing Toxicological Profiles.     

水蛭和海马中17种有机氯农药的残留分析

［摘要］目的对气相色谱分析动物药材水蛭、海马中17种有机氯农药残留量的方法进行适用性实验，并初步调查这两种动物药中农药残留的状况。方法从全国药材市场收集样品，样品以丙酮 石油醚（1：1）超声提取，提取液浓缩后用浓硫酸净化，采用DB 1701石英毛细管柱分离样品，GC ECD测定17种有机氯农药的残留量。结果17种农药2个水平的平均添加回收率分别为75.3%，88.1%。两种动物药中都检测到了农药残留，其中水蛭药材样品中的滴滴涕含量较高。结论该方法适用于动物药水蛭和海马中农药残留的测定，动物药中的残留农药污染和蓄积应引起重视。