Chronic dietary risk characterization for pesticide residues: A ranking and scoring method integrating agricultural uses and food contamination data

A method has been developed to identify pesticide residues and foodstuffs for inclusion in national monitoring programs with different priority levels. It combines two chronic dietary intake indicators: ATMDI based on maximum residue levels and agricultural uses, and EDI on food contamination data. The mean and 95th percentile of exposure were calculated for 490 substances using individual and national consumption data. The results show that mean ATMDI exceeds the acceptable daily intake (ADI) for 10% of the pesticides, and the mean upper-bound EDI is above the ADI for 1.8% of substances. A seven-level risk scale is presented for substances already analyzed in food in France and substances not currently sought. Of 336 substances analyzed, 70 pesticides of concern (levels 2-5) should be particularly monitored, 22 of which are priority pesticides (levels 4 and 5). Of 154 substances not sought, 36 pesticides of concern (levels 2-4) should be included in monitoring programs, including 8 priority pesticides (level 4). In order to refine exposure assessment, analytical improvements and developments are needed to lower the analytical limits for priority pesticide/commodity combinations. Developed nationally, this method could be applied at different geographic scales.     

Prioritization of pesticides based on daily dietary exposure potential as determined from the SHEDS model

A major pathway for exposure to many pesticides is through diet. The objectives were to rank pesticides by comparing their calculated daily dietary exposure as determined by EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) to single pesticides for different age groups to acceptable daily intakes (ADI), characterize pesticide trends in exposures over different time periods, and determine commodities contributing to pesticide exposures. SHEDS was applied, using Pesticide Data Program (PDP) (1991–2011) and pesticide usage data on crops from USDA combined with NHANES dietary consumption data, to generate exposure estimates by age group. ADI data collected from EPA, WHO, and other sources were used to rank pesticides based on relativeness of the dietary exposure potential to ADI by age groups. Sensitivity analysis provided trends in pesticide exposures. Within SHEDS, commodities contributing the majority of pesticides with greatest exposure potential were determined. The results indicated that the highest ranking pesticides were methamidophos and diazinon which exceeded 100% of the ADI. Sensitivity analysis indicated that exposure to methamidophos, diazinon, malathion, ethion and formetanate hydrochloride had a marked decrease from 1991–1999 to 2000–2011. Contributions analysis indicated that apples, mushroom, carrots, and lettuce contributed to diazinon exposure. Beans and pepper contributed to methamidophos exposure.     

Risk assessment of mixtures of pesticides. Current approaches and future strategies

The risk assessment of pesticide residues in food is based on toxicological evaluation of the single compounds and no internationally accepted procedure exists for evaluation of cumulative exposure to multiple residues of pesticides in crops, except for a few groups of pesticides sharing a group ADI. However, several attempts have been suggested during the last decade. This paper gives an overview of the various approaches. It is of paramount importance to consider whether there will be either no interaction or interaction between the compounds in the mixture. When there are no interactions several approaches are available for the risk assessment of mixtures of pesticides. However, no single simple approach is available to judge upon potential interactions at the low doses that humans are exposed to from pesticide residues in food. In these cases, PBTK models could be useful as tools to assess combined tissue doses and to help predict potential interactions including thresholds for such effects. This would improve the quality of the risk assessment.     

Estimation of risks of pesticide exposure, by food intake, to Koreans.

The aim of this study was to evaluate theoretical maximum daily intake (TMDI) and estimated daily intake (EDI) for Korean by using maximum residue levels (MRLs), food intake, residue data and correction factors, and compare with acceptable daily intake (ADI) in order to estimate the health risk based on the pesticide exposure. Then, the oncogenic risks of the pesticides were assessed from TMDI and estimated daily intake with treatment (adjusted EDI). The percent ratio of TMDI to ADI for 262 pesticides was mostly below 80%, but 42 pesticides (16.0%) exceeded the ADI. EDI without treatment (non-adjusted EDI) and estimated daily intake with treatment (adjusted EDI) were summed up to about 6.41 ml/day/capita and 2.94 ml/day/capita, respectively. The percentage of ADI was TMDI (101.04%) > non-adjusted EDI (0.08%) > adjusted EDI (0.01%), and the exposure level of Korean population to whole pesticides was below the level to produce health risk. The dietary oncogenic risk for Koreans was estimated to be 7.3x10(-4) on the basis of TMDI, 1.8x10(-7) on the basis of adjusted EDI, and although the level from TMDI exceeded the risk level (1x10(-6)) of the Environment Protection Agency (EPA), the level from adjusted EDI, real exposure level, was below it.     

A retrospective analysis of the added value of 1-year dog studies in pesticide human health risk assessments

The 1-year dog toxicity study is no longer required by certain pesticide regulatory jurisdictions, including the United States and the European Union. Health Canada’s Pest Management Regulatory Agency (PMRA) examined its current requirement for this study to determine if it could be refined or eliminated. A retrospective analysis was conducted to examine the impact of the 1-year dog study on human health risk assessment. The Acceptable Daily Intake (ADI), a measure of the amount of a pesticide in food that can be ingested on a daily basis over a lifetime without an appreciable health risk, was the metric for this analysis. For 143 pesticides evaluated by the PMRA between 2008 and 2015, the supporting toxicology databases were examined to determine if other toxicology studies were protective of the findings in the 1-year dog study. When this criterion was not met, further investigation was undertaken to determine the potential impact of not having the 1-year dog study. For most of the pesticides, effect levels in the 1-year dog study were not substantially different from those in other toxicology studies, when considering factors such as dose-spacing and known experimental variability. The results of this analysis suggest that absence of the 1-year dog study would have minimal impact on the assessment of human health risk. Therefore, Health Canada’s PMRA has removed the routine requirement for the 1-year dog study from its pesticide data requirements.     

Monitoring and risk assessment of pesticides in fresh omija (Schizandra chinensis Baillon) fruit and juice

Schizandra chinensis Baillon, or omija, is a fruit native to northeast Asia that is cultivated in South Korea and China. Fresh omija fruit has been used in beverages, traditional East Asian medicine and cosmetics because of its complex flavor and pharmacological effectiveness. The objective of this study was to analyze residue levels of 33 kinds of pesticides on fresh omija fruits and in omija juices produced in South Korea. A risk assessment of the pesticides in omija juice was conducted by calculating EDI and ADI. Most of the pesticide levels were below the LOD in fresh omija fruits. Among the detected compounds, the most frequently detected pesticide was ethoprophos. The EDIs of ethoprophos, pendimethalin and hexaconazole were 5.89E-03, 7.08E-04 and 4.73E-05, respectively. The percent of EDI to ADI of ethoprophos, pendimethalin and hexaconazole was 28.0%, 13.6% and 4.5%, respectively. The results of this research concluded that the detected pesticides are not harmful to human beings.     

The significance of the subchronic toxicity in the dietary risk assessment of pesticides

Based on 289 public pesticide evaluations, geometric means of subchronic/chronic No Observed Adverse Effect Level (NOAEL) ratios of 2.6, 2.5 and 1.6 in mice, rats and dogs were calculated. The 75th percentiles are 5.5, 5.1 and 3.2. Higher ratios correlate with increased dose spacing in chronic studies and may be mainly explained therewith. In rats fed at constant pesticide concentrations in feed, the mean chronic dose decreases by 1.7- and 2.7-fold compared to the subchronic and subacute phase. These dose decreases match the subchronic/chronic NOAEL ratios. The ratio of predicted rat chronic NOAEL (dose decrement adjusted subchronic NOAEL) to experimental chronic NOAEL is 1.5 and the 75th percentile is 3.0. In dietary risk assessment, the Acute Reference Dose and the Acceptable Daily Intake (derived from acute and chronic NOAEL) are compared to acute (IESTI) or mean (TMDI) exposure estimates. Because IESTI and TMDI base on acute or mean food consumption they differ by orders of magnitude for certain commodities. As subchronic and chronic NOAEL are similar, it remains to be shown whether pesticide intake estimates based on mean food consumption are adequate measures to compare against the ADI if repeated daily exposures considerably higher than mean exposures may occur.     

Intake assessment for benzoates in different subgroups of the Flemish population.

An exposure assessment was performed to estimate the daily intake of benzoates for the Flemish population. Three age groups were considered: preschool children (n=697; age 2-6; 3-day estimated dietary record), adolescents (n=341; age 14-18; 7-day estimated dietary record) and women (n=641; age 18-40; 2-day estimated dietary record). In a first step in the risk evaluation process as proposed by the European Union, the individual food consumption data were multiplied with the maximum permitted use levels for benzoates per food group. The median (interquartile range) estimated daily intake is, respectively, 2.0 (1.0-3.2) mg/kg bw, 1.7 (1.1-2.7) mg/kg bw and 1.92 (1.3-3.0) mg/kg bw for preschool children, adolescents and adult women. In all age groups, the greatest potential contributor to the total estimated benzoate intake was the group of non-alcoholic flavoured drinks. At respectively the 92nd percentile (children), the 97th percentile (adolescents) and the 94th percentile (women), the accepted daily intake (ADI) of 5mg/kg bw/day is exceeded slightly. However, this approach, in which the maximum permitted use levels are used is known to overestimate the intake, since not all food items in which benzoates are allowed, contain (the maximum permitted use level of) benzoates. A more precise estimation, using actual levels, is recommended.     

Dietary exposure of Brazilian consumers to dithiocarbamate pesticides--a probabilistic approach.

A probabilistic estimation of the exposure of the Brazilian population to the dithiocarbamate pesticides was performed using the Monte Carlo Risk Assessment program (MCRA 3.5). Residue data, as CS2, for 3821 samples were obtained from the Brazilian national monitoring program on pesticide residues and from the monitoring program conducted in the Distrito Federal on rice, beans and nine fruits and vegetables. Food consumption data were obtained from a Brazilian household budget survey conducted between 2002 and 2003. Processing factors for washing, peeling or cooking were applied to the residues found in the crops. Daily intakes at the highest percentiles for the general population reached a maximum of 2.0 microg CS2/kg body weight per day (upper band of the 95% confidence interval at P99.99). Tomato, rice, apple and lettuce were the commodities which contributed most to the intake. Based on the registered uses and the toxicological profile of dithiocarbamates, the risk from exposure was evaluated assuming that all residues came from the use of ethylene-bis-dithiocarbamate (EBDC) or that a fraction of it came from the use of propineb. For this last scenario, a cumulative risk assessment was conducted. In the first scenario, the highest intake reached up to 11.9% EBDC ADI for the general population and up to 31.1% ADI for children. When 30% of the residues were considered as coming from propineb use, the values were 15.2% and 39.7% ADI, respectively.     

The presence of dialkylphosphates in fresh fruit juices: implication for organophosphorus pesticide exposure and risk assessments

This study was designed to determine whether dialkylphosphates (DAPs) are present in fresh fruit juices, as a result of organophosphorus (OP) pesticides degradation. Fresh conventional and organic fruit (apple and orange) juices were purchased from local grocery stores. DAPs were found in both conventional and organic juices, and the original levels were higher, for both apple and orange juices, in conventional than in organic juices. Additional DAPs were found in OP pesticide fortified juices after 72 h of storage at 4 degrees C, suggesting a degradation of OP pesticides in juices. Overall, 12% and 36.2% of fortified azinphosmethyl, a dimethyl OP pesticide, and the combination of fortified diazinon and chlorpyrifos, both diethyl OP pesticides, were degraded to dimethyl and diethyl DAPs, respectively. Although the exact mechanism of the degradation is unknown, hydrolysis is likely the cause of OP pesticide degradation in juice. The presence of DAPs in fresh fruit juices clouds the validity of using urinary DAP measurements for estimating OP pesticide exposures in humans, particularly in children. The overestimated OP pesticide exposures based on urinary DAPs reported in other studies is likely due to the coexistence of preformed DAPs and DAPs resulting from OP pesticide exposures. Thus, before urinary DAP concentrations can be reliably used in exposure and risk assessment, the proportion of the concentration attributable to environmental DAP exposure, particularly through the diet, must be ascertained. In conclusion, urinary DAPs have many limitations when being used as biomarkers for OP pesticides in exposure and risk assessment, and caution should be exercised when interpreting DAPs results.     

Study parameters influencing NOAEL and LOAEL in toxicity feeding studies for pesticides: exposure duration versus dose decrement, dose spacing, group size and chemical class

The effect of exposure duration on no observed adverse effect levels (NOAEL) and lowest observed adverse effect levels (LOAEL) in rodent pesticide feeding studies was evaluated. Ratios of NOAEL (and LOAEL), expressed as pesticide concentrations in feed, were calculated from subacute to subchronic, subchronic to chronic and subacute to chronic studies. There was no statistical significant effect of exposure duration on ratio distributions. Whereas geometric means of ratios were in a narrow range of 1.1–2.5, the geometric standard deviations and 95th percentiles increased with dose spacing of the involved studies. With the exception of carbamates, the chemical class of pesticides had no influence on the ratio distributions. However, the number of animals in the shorter-term study of ratio couples being ?1 was statistically significantly higher than in ratio couples being >1. Ratios ?1 may be partly explained by the dose decrement over time observed in feeding studies applying the test substances in constant concentrations. The dose decrement possibly converts initially toxic doses to less toxic doses beyond the subacute phase. Ratios >1 seem to be caused predominantly by differences in study design parameters. In dietary risk assessment, the acceptable daily intake (ADI) is compared to pesticide intake estimates based on mean food consumption (i.e. the so called theoretical maximum daily intake, TMDI) being orders of magnitude lower than actual food consumption on eating occasions for certain food commodities. As subacute, subchronic and chronic NOAEL (and LOAEL), expressed as pesticide concentration in feed did not differ statistically significantly, the TMDI as benchmark for the ADI may underestimate the significance of the toxicity of subacute exposure.     

Food contamination by metals and pesticides in the European Union. Should we worry?

The estimation of the risk associated with dietary intakes of heavy metals and pesticide residues by the consumer is a vital and integral part of regulatory processes. The exposure of the consumer is compared directly to the acceptable daily intake (ADI) for pesticides and to the tolerable daily intake (TDI) for heavy metals. The exposure is obtained using the basic equation: Exposure (mg/kg b.w./day)=Consumption (mg/kg b.w./day) x Residue (mg/kg). The establishment of the ADI and the TDI is based on the results of toxicological studies that involve the determination of the lowest-no-observed-adverse-effect level/10 (SF1) x10 (SF2), where SF corresponds to 'Safety Factor'. SF1 and SF2 account for interspecies and intraspecies variability, respectively. In order to evaluate the risk for the consumer, that is associated to the presence of heavy metals and pesticides in food, a review of the level of contamination in European countries has been made. The exposure of European consumers to lead, cadmium, arsenic and mercury is superior to the TDI. For pesticides, the first step is to compare the detected amount of residues of a specific pesticide to the maximum residue level (MRL) authorized in foodstuffs. If the residue level in food exceeds the MRL, the theoretical maximum daily intakes and the ADI have to be taken into account in order to assess the risk for the consumer.     

Probabilistic assessment of the cumulative acute exposure to organophosphorus and carbamate insecticides in the Brazilian diet

In the present study, the cumulative exposure of 25 acetylcholinesterase (AChE) inhibiting pesticides through the consumption of nine fruits and vegetables by the Brazilian population was assessed. Food consumption data were obtained from a household budget survey conducted in all Brazilian states from July 2002 to June 2003. Residue data from 4001 samples were obtained from the Brazilian national monitoring program on pesticide residues. Relative potency factors (RPF) were calculated with methamidophos or acephate as index compounds (IC), using BMD(10) or NOAEL for AChE inhibition, mostly in rat brain, obtained from national and international pesticide evaluations. Monocrotophos and triazophos, in addition to aldicarb, had the highest calculated RPF in any scenario. The exposure to AChE inhibiting pesticides for the general population at P99.9, represented 33.6% of the ARfD as methamidophos and 70.2% ARfD as acephate. The exposure calculated as acephate could exceed the ARfD at the upper bound of the 95% confidence interval for this percentile. Exposure for children aged up to 6 years were, on average, 2.4 times higher than the exposure for the general population. Tomato represented about 67% of the total intake of AChE inhibiting pesticides. The highest calculated equivalent residues in tomato, which drove most of the estimated intakes at the high percentiles, were related to the illegal use of monocrotophos and triazophos in this crop.     

Cumulative risk assessment of the exposure to pyrethroids through fruits consumption in China – Based on a 3-year investigation

In the present study, the long-term and short-term cumulative risks of pyrethroids exposured for the Chinese general population and children through fruits consumption were evaluated. A total of 1450 fruit samples and seven pyrethroids were included based on the pesticide residues monitoring programme of China from 2013 to 2015. The exposure was estimated using both deterministic approach and semi-probabilistic model for comparison. The hazard index approach was used to assess cumulative risk. 26% of samples contained pyrethroid residues with concentrations ranged from 0.0050 mg/kg to 1.2 mg/kg, of which 30% simultaneously with 2–4 mixture residues. Results demonstrated that the cumulative health risks were extremely low for both general population and children (1–6 years old) of China in the long term. Acute risk estimations calculated by deterministic method were several or many times overestimated than the results based on semi-probabilistic method. Acute cumulative exposure of children to pyrethroid compounds in 0.76% samples were exceeded 1 in worst case scenario. More detailed assessments with adequate data in the future use probabilistic method is expected to reduce the uncertainties of cumulative dietary exposure.     

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。     

Estimates of the theoretical maximum daily intake of erythorbic acid, gallates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in Italy: a stepwise approach

The three recent EU directives which fixed maximum permitted levels (MPL) for food additives for all member states also include the general obligation to establish national systems for monitoring the intake of these substances in order to evaluate their use safety. In this work, we considered additives with primary antioxidant technological function for which an acceptable daily intake (ADI) was established by the Scientific Committee for Food (SCF): gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and erythorbic acid. The potential intake of these additives in Italy was estimated by means of a hierarchical approach using, step by step, more refined methods. The likelihood of the current ADI to be exceeded was very low for erythorbic acid, BHA and gallates. On the other hand, the theoretical maximum daily intake (TMDI) of BHT was above the current ADI. The three food categories found to be main potential sources of BHT were “pastry, cake and biscuits”, “chewing gums” and “vegetables oils and margarine”; they overall contributed 74% of the TMDI. Actual use of BHT in these food categories is discussed, together with other aspects such as losses of this substance in the technological process and percentage of ingestion in the case of chewing gums.     

Human health risk assessment from the presence of human pharmaceuticals in the aquatic environment

Assessments for potential impact to human health from environmental exposures were carried out for 44 active pharmaceutical ingredients (APIs) marketed by GlaxoSmithKline (GSK), representing approximately 22 general pharmacological classes exhibiting a broad spectrum of therapeutic activities. These assessments use the considerable amount of information available on the human pharmacology and toxicology of the APIs to develop acceptable daily intakes (ADIs) which are believed to be without pharmacological or toxicological effect. With the exception of the anti-cancer drugs and some antibiotics, the minimum dose producing the intended therapeutic effect was typically used as the point of departure for calculation of ADIs. The ADI values were used to generate predicted no effect concentrations from environmental exposure for human health (PNEC_HHs) from drinking water or fish consumption. These PNECs were compared to predicted environmental concentrations (PECs) calculated using the regional assessment models PhATE™ for North America and GREAT-ER for Europe. Risk was characterized by calculating the ratio of the 90th percentile PECs to the PNEC_HHs. For the APIs reported here, these ratios are less than one for all of the compounds, varying from 7 × 10⁻² to 6 × 10⁻¹¹, indicating that based upon currently available data, these compounds do not appear to pose an appreciable risk to human health from potential environmental exposure from drinking water and fish consumption.     

Health risk of low-dose pesticides mixtures: a review of the 1985-1998 literature on combination toxicology and health risk assessment

A literature review covering the last 14 yr has been performed in the field of combination toxicology and human risk assessment from exposure to chemical mixtures, with special emphasis on mixtures of pesticides at low doses, that is, at levels likely to occur in human diet and environment. Despite a large body of knowledge in the field of risk assessment methodologies for exposure to chemical and pesticide mixtures, there is no single methodological approach in "combination toxicology" and health risk assessment of chemical mixtures, and therefore professional judgment is still required. Generally, the dose or response additivity approach that may be applied to evaluate potential risk for chemical mixtures in human toxicology overestimates the risk of a combination of chemicals. The recent endocrine disrupter issue demonstrated the difficulty of reproducibility of data when testing environmental toxicants at very low levels, and the need for more basic work in this field. The use of integrated methodological approaches may provide more reliable predictive data in the risk assessment of chemical mixtures in future. Yet data have demonstrated that exposure to a combination of compounds does not cause effects stronger than the ones of their most active component, provided components are present at low concentration levels, like acceptable daily intake (ADI) or reference dose (RfD) levels, well below their respective no-observed-adverse-effect levels (NOAELs). Although it has been demonstrated that a combination of compounds with the same target organ and the same or very similar mechanisms of action may cause additive or synergistic effects, the chance of such effects will most likely diminish with decreasing exposure levels to such combinations. Synergism and antagonism may both occur at the same time at different organs or targets in the same organism. However, and despite some exceptions, it has been demonstrated that interaction between components is not a common event at low levels of human exposure such as those that may occur through pesticides residues in food or drinking water. The introduction of a special safety factor as a standard for mixtures in addition to those normally used for deriving ADIs, RfDs, or minimal risk levels is not supported by data. It can be concluded from our review that, as a general rule, exposure to mixtures of pesticides at low doses of the individual constituents does not represent a potential source of concern to human health.     

HEALTH RISK OF LOW-DOSE PESTICIDES MIXTURES: A Review of the 1985-1998 Literature On Combination Toxicology and Health Risk Assessment

A literature review covering the last 14 yr has been performed in the field of combination toxicology and human risk assessment from exposure to chemical mixtures, with special emphasis on mixtures of pesticides at low doses, that is, at levels likely to occur in human diet and environment. Despite a large body of knowledge in the field of risk assessment methodologies for exposure to chemical and pesticide mixtures, there is no single methodological approach in "combination toxicology" and health risk assessment of chemical mixtures, and therefore professional judgment is still required. Generally, the dose or response additivity approach that may be applied to evaluate potential risk for chemical mixtures in human toxicology overestimates the risk of a combination of chemicals. The recent endocrine disrupter issue demonstrated the difficulty of reproducibility of data when testing environmental toxicants at very low levels, and the need for more basic work in this field. The use of integrated methodological approaches may provide more reliable predictive data in the risk assessment of chemical mixtures in future. Yet data have demonstrated that exposure to a combination of compounds does not cause effects stronger than the ones of their most active component, provided components are present at low concentration levels, like acceptable daily intake (ADI) or reference dose (RfD) levels, well below their respective no-observed-adverse-effect levels (NOAELs). Although it has been demonstrated that a combination of compounds with the same target organ and the same or very similar mechanisms of action may cause additive or synergistic effects, the chance of such effects will most likely diminish with decreasing exposure levels to such combinations. Synergism and antagonism may both occur at the same time at different organs or targets in the same organism. However, and despite some exceptions, it has been demonstrated that interaction between components is not a common event at low levels of human exposure such as those that may occur through pesticides residues in food or drinking water. The introduction of a special safety factor as a standard for mixtures in addition to those normally used for deriving ADIs, RfDs, or minimal risk levels is not supported by data. It can be concluded from our review that, as a general rule, exposure to mixtures of pesticides at low doses of the individual constituents does not represent a potential source of concern to human health.