Acute Reference Dose

In September 1999, the United Nations World Health Organization (WHO) and the Food and Agriculture Organization (FAO) Joint Meeting on Pesticide Residues (JMPR) established an acute reference dose (RfD) of 0.1 mg/kg bw and a chronic RfD, or acceptable daily intake (ADI), of 0.01 mg/kg bw/day. (See FAO/WHO Report 153, Pesticide Residues in Pood, Section 4.7, Chlorpyrifos, 1999.)... 

The term acceptable is used widely to describe safe levels of intake and is apphed for chemicals to be used in food production such as, e.g., food additives, pesticides, and veterinary dmgs. The term tolerable is applied for chemicals unavoidably present in a media such as contaminants in, e.g., drinking water and food. The term PTWI (Provisional Tolerable Weekly Intake) is generally used for contaminants that may accumulate in the body, and the weekly designation is used to stress the importance of limiting intake over a period of time for such substances. The tolerable intake is similar in definition and intent to terms such as Reference Dose and Reference Concentration (RfD/RfC), which are widely used by, e.g., the US-EPA. For some substances, notably pesticides, the ARID (Acute Reference Dose), is also established, often from shorter-term studies than those that would support the ADI. The ARfD is defined as the amount of a substance in food that can be consumed in the course of a day or at a single meal with no adverse effects. 

When proposing an MRL, the Rapporteur Member State (RMS) identifies the Acceptable Daily Intake (ADI) and Acute Reference Dose (ARfD) for man that is valid for the pesticide in question. The ADI thus identified is often the same as that recommended by the Joint FAO/WHO Meetings on Pesticide Residues (JMPR), whose recommendations on ADIs and MRLs are used within the Codex Alimentarius system. If the ADI proposed by the RMS is not that recommended by JMPR, the RMS has to provide an explanation for the difference. The other Member States comment on the RMS proposal at meetings of the Working Group on Pesticide Residues. If the Member States cannot reach agreement on the evaluation, the matter is referred to one or more of the Commission s scientific advisory committees. Prior to autumn 1997, such questions were referred to the Scientific Committee for Pesticides, but since then they have been referred to the Scientific Committee on Plants. 

All of the previously mentioned exposure methods can be used to estimate either chronic exposure (over a period of years) or acute exposure (single day) for the United States population and population subgroups. Both chronic and acute assessments are usually based on a no observed adverse effect level (NOAEL) in an animal species. Acute exposure is defined relative to an acute (single dose) toxicological endpoint (usually a NOAEL) and may be expressed as a margin of exposure (MOE) or as a percentage of an acute reference dose that is based on a NOAEL and an uncertainty factor (see below). 

JMPR (2004) Guidance on the establishment of acute reference doses. In Pesticide residues in food — 2004. Report of the Joint WHO/FAO Meeting on Pesticide Residues 2004. Rome, Food and Agriculture Organization of the United Nations (FAO Plant Production and Protection Paper 178). 

Solecki R, Davies L, DeMarco V, Dewhurst I, Raaij M, Tritscher A (2005) Guidance on setting of acute reference dose (ARfD) for pesticides. Food Chem Toxicol, 43(11) 1569-1593. 

Several assessments were conducted to illushate the impact of different procedures on dietary risk assessment. In all cases, consumption data from the UK surveys were used. One of the differences between the US and the EU is the food consumption data. However, conducting assessments with both US and UK food consumption data will confound the comparisons, so the assessments will be run using only the UK food consumption data. All exposure estimates are presented as percent of the chronic Reference Dose (cRiD) of 0.005 mg/kg bw/day or the acute Reference Dose (aRfD) of 0.01 mg/kg bw/day (both toxicity values are hypothetical for illushative purposes). 

To date, JMPR has evaluated 240 pesticides, many of them repeatedly. JMPR establishes ADIs (based on chronic toxicity) and acute reference doses (based on acute toxicity) on the basis of the toxicological data and related information available on the substances that are being evaluated. In addition, JMPR reviews pesticide use patterns, data on the chemistry and composition of pesticides, and methods of analysis of pesticide residues. It recommends MRLs for pesticides that occur in food commodities following their use according to Good Agricultural Practice. The potential intake of pesticide residues is compared with the ADI and acute reference dose to estimate the potential dietary risks associated with the adoption of the MRLs. 

The acute reference dose is 0.001 mg kg and the chronic reference dose is 0.0001 mgkg day ... 

US Environmental Protection Agency has established an acute reference dose of 0.000 25 mg kg day and a chronic reference dose of 0.0000 33 mg kg day for parathion. 

TABLE 3, WHO/FAO Recommended Acute Reference Dose (RfD) of OP and CM Pesticides ... 

However, the Expert Consultation decided that there are currently insufficient data to complete a risk assessment and establish an acute reference dose for brevetoxins. There are uncertainties about the true exposure for the different analogues and metabolites of brevetoxins associated with the reported NSP episodes. 

A lowest observable adverse effect level (LOAEL) was estimated to be 1.2-1.6 pg/kg, on the basis of human poisoning in Japan (eight people from three families, aged 10-68). In another stndy from Norway, 38 of 70 adults were affected at levels ranging from 1.0 to 1.5 pg/kg. From these data, a provisional acute reference dose (RfD) of 0.33 pg OA equivalents/kg (based on the LOAEL of 1.0 mg OA/kg and a safety factor of 3) was established (for details, see Reference 15). 

The recent data on the oral toxicity of PTX-2, -11, and -2 seco acid allow comment on the acute reference doses of these compounds and hence tolerable levels for their presence in shellfish. No effects were recorded with any of these compounds after admiiustration to mice by gavage at 5000 Tg/kg. The lethal dose of these compounds is therefore greater than 5000 [tg/kg. Application of the standard 100-fold safety factor [63] gives a dose of >50 [ig/kg as a predicted non toxic acute dose for a human. This equates to >3000 Tg for a 60 kg adult, and if a shellfish intake of 380 g in a single meal is assumed, the predicted safe level in shellfish is >7.9 mg/kg. 

Renwick A.G. The use of safety or uncertainty factors in the setting of acute reference doses, Eood Addit. Contam. 17, 621, 2000. 

In the case of gymnodimine, the acute toxicity by feeding was >7500 [tg/kg. By application of a safety factor of 100, the acute reference dose would be 75 [tg/kg body weight, equivalent to a dose... 

Chemicals (lOMC), 2010, OECD Environment, Health, and Safety Publications Series on Testing and Assessment 124, Guidance for the Derivation of an Acute Reference Dose, Env/JM/MONO(2010)15 (available at http //www.oecd. org/officialdocuments/displaydocumentpdf cote= env/jm/mono (2010) 15 doclanguage=en accessed... 

---