Residue limits acceptable daily intake

Maximum residue limits have been recommended by the Joint FAO/WHO Meeting on Pesticide Residues. An acceptable daily intake of 0-0.02 mg kg body weight was established for fenvalerate by JMPR in 1986. 

Field residues, if below the toxicological limit (acceptable daily intake), are used to set the legal limit. The residues of pesticides in the field experiment are affected by the environmental conditions such as temperature, wind, rain, solar irradiance etc. For this reason, residues limits (MRLs) can vary between countries because of the different climatic conditions, leading to EU trade difficulties. 

Pesticide residues were analyzed in 183 milk samples from 165 Finnish women. Heptachlor was found in 12% of the samples heptachlor epoxide was found in 6.6%. Five percent of the samples contained levels of heptachlor epoxide in excess of 0.0005 mg/kg body weight, an acceptable daily intake (Mussalo-Rauhamaa et al. 1988). Fifteen milk and fat specimens from residents of Grand Forks, British Columbia, and 16 milk and 17 fat specimens from residents of Prince George, British Columbia, were analyzed for pesticide residues. Heptachlor epoxide was found in one milk sample and nine fat samples in the Grand Forks group (>0.004 ppm) and in no milk samples and two fat samples in the Prince George group (>0.004 ppm) (Larsen et al. 1971). The residue was not detectable at levels lower than 0.004 ppm because of limitations of the analytical methods and faulty techniques. It is possible that the potential exposure of the residents to heptachlor may also have occurred via food contaminated with heptachlor. 

Table 11.1 Maximum Residue Limits (MRLs) and Acceptable Daily Intake (ADI) for Veterinary Medicinal Products in Foodstuffs of Animal Origin According to the Codex Alimentarius... 

Some critical differences in risk assessment procedure lead to confusing situations on a worldwide basis. These differences are due to some very controversial areas of safety issues including the calculation of the acceptable daily intake (ADI), the assignment of the ADI to maximum residue limit (MRL)/tolerance, the validation of the analytical methods needed to regulate drug residues, and the fitness of legislation to toxicology. 

In June 1987, the JECFA established acceptable daily intake levels and acceptable residue limits for zeranol and trenbolone acetate and decided that these levels were not needed for the naturally occurring hormones. With respect to the natural hormones, the JECFA explained that residues resulting from use of these... 

This method of calculation is based on the use of animal toxicity data to determine limits. As mentioned earlier, this method is particularly suited for determining limits for materials that are not used medically. This method is based upon the concepts of acceptable daily intake (ADI) and no observed effect level (NOEL) developed by scientists in the Environmental Protection Agency [7], the U.S. Army Medical Bioengineering Research and Development Laboratory [8], and the toxicology department at Abbott Laboratories [9], This method has also been recently used to calculate the limits of organic solvent residues allowed in APIs [10]. 

In this equation ARL is the acceptable residue limit, ADI is the acceptable daily intake, SBS is the smallest batch size, SA is the swab surface area, CF is the conversion factor (1000), MDD is the maximum daily dose of product B, and SSA is the shared surface area. At first glance, this calculation has desirable attributes of both the 10 ppm method and the 1/1000 method. For example, the 1/1000th method and the TTC method take into account the maximum daily dose of product B. Likewise the 10 ppm method and the TTC method take into account the lot size of product B. The main difference between the calculations is that the ADI is justified... 

For residues (such as cleaning agents) that do not have a defined dose, some measure of toxicity, such as an acceptable daily intake (ADI), is used for residue limit purposes. If the subsequently manufactured product is an in vitro diagnostic (IVD), and has no defined dose, then some evaluation of the effects of target residues on the performance or stability of the IVD product should be performed. These non-dose factors are used only for the Li limit there are no changes for calculation of L2 and L3 limits. 

Specialists invited to serve as members of JECFA are independent scientists who serve in their individual capacities as experts and not as representatives of their governments or employers. They also understand that the discussions at the meetings are confidential. The goal is to establish acceptable daily intakes (ADIs) (or equivalent tolerable intakes) for food chemicals and to develop specifications for identity and purity for food additives or maximum residue limits (MRLs) when veterinary drugs are used in accordance with good practice in the use of veterinary drugs. 

The assessment of these compounds and the establishment of an ADI (acceptable daily intake), to be explained later, or MRL (maximum residue limit) are carried out by an international committee of the WHO (Joint Meeting on Pesticide Residues). The World Health Organization publishes toxicological and ecotoxicological evaluations of potential environmental toxicants in the International Proceedings on Chemical Safety in the series "Environmental Health Criteria."... 

The enforcement of this legislation has led to an increasing need from analysts to develop reliable, effective methods for qualitative and quantitative pesticide residue analysis in environmental and food matrices. EEC Directive 80/778, which is concerned with the quality of water designated for human consumption, has established the maximum admissible concentration of each individual pesticide at 0.1 /rg/l and the total amount of pesticides at 0.5 /rg/1. Other countries (e.g., U.S.A. and Australia) have established concentration limits based on the values recommended by WHO. Such values are based on the acceptable daily intake (ADI), which is calculated as the 20% ADI for a person of 70 kg drinking 2 1 of water per day. "... 

JECEA is an independent expert committee established (and jointly administered) by the FAO and the WHO in 1956 to evaluate the safety of food additives. Uie work has since expanded to include the evaluation of the safety of contaminants, naturally occurring toxicants and residues of veterinary drugs in food. JECFA serves as the risk assessor for the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF), establishing an acceptable daily intake (ADI) for a veterinary drug when sufficient information is available, recommending maximum residue limits (MRLs) for consideration by... 

Finally, it should be mentioned that there are tables comprising the limits that FAO/WHO have determined regarding the acceptable daily intake (ADI) and the maximum residue limits (MRLs). 

The scientific committees mentioned earlier assess the safety for consumers of foods derived from animals treated with coccidiostats by assessing the available data from studies of the pharmacokinetics (including metabolism and residue depletion) in the target species and laboratory animals, toxicological studies and any available observations in exposed humans. Consumer safety is expressed numerically as an acceptable daily intake (ADI) and legal limits applied to concentrations of residues permitted in foods are established as a... 

Chlorpromazine was used in food animals in the European Union (EU). When the information was reviewed in order to establish maximum residue limits (MRLs) for the drug, it was concluded that there were insufficient data to allow the identification of a no-observed effect level and no acceptable daily intake could be calculated. Hence, the drug was prohibited for use in food animals in the EU. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) considered MRLs for chlorpromazine and another phenothiazine drug propionylpromazine. It too considered the available data to be inadequate and was unable to establish MRLs for either compound. 

ICH Q3C guides in determining, on a safety basis, acceptable residual solvent levels for intake by use of the term permitted daily exposure (PDE). This Guidance classifies residual solvents used in the synthesis and processing into four categories. The Guidance recommends that Class I solvents be avoided. These include benzene, carbon tetrachloride, 1,2-dichloromethane, 1,1-dichloroethane, and 1,1,1-trichloroethane. Table 2 is an example from the list of Class II solvents that should be limited because of their inherent toxicity either by calculation of concentration (PPM) or by PDE. 

This question of whether it is scientifically valid to derive the lifetime control limit by using threshold or non-threshold models defines what cleanup levels are proposed for a site. The action level proposed by CDC for residential soil in Missouri is 1 ppb, based on a series of exposure assumptions and on virtually safe doses for 10"° cancer risk of 0.0276 pg/kg/day (U). If one assumes a different threshold - based model, as did Dutch, Swiss, German, and Canadian workers (9), one obtains maximum allowable daily intake of 1-10 pg/kg/day. If one uses the same exposure calculations as CDC, one could then accept 4-40 ppb in residential soil according to these allowable daily intakes. CDC and ERA have allowed 7 ppb as acceptable residual concentrations at an industrial site in New Jersey (IJ). At Seveso, cleanup levels were set at 45 ppt for nonagricultural soil and 7 ppt for agricultural soil... 

Provided the test compound does not result in any residues exceeding 0.1 ppm on food crops, applicator exposxire is minimal, and the limited toxicity data indicate that the negligible daily intake (i.e. that dose below which intake, on a daily basis for a lifetime is considered to be toxicologically insignificant -usually a dose level of l/lOOOth of the "no observable effect level" on the most sensitive toxicological parameter examined, in the most sensitive species) will not be exceeded it is possible that registration would be recommended. The tendency is, however, to require considerably more data than the minimum acceptable package described above. 

After these introductory remarks, I shall attempt to give you an account of the current recommendations of the World Health Organization in this field. In particular, I will stress the "safe" levels of intake based on concepts such as Acceptable and Admissible Daily Intake (ADI), respectively, for intentional food additives and pesticide residues in food Provisional Tolerable Weekly Intake (PTWI) for cumulative toxic metals figures for body burdens and the corresponding "safe" limits recommended for foodstuffs, including the relatively recent definition of irreducible limits to deal with the problem of trace contaminants in food. 

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