Toxicity, acute Reference Dose

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 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. 

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... 

Acute toxicity In vitro Mammalian systems Aquatic vertebrates and invertebrates Plants IC/EC50 in appropriate test species Use of appropriate indicators of acute toxicity, for example, EPA guidance values, reference doses, and so on... 

The ERA has calculated a subchronic oral reference dose (RfD) of 7x10 mg/kg/day for carblon tetrachloride based on a NOAEL of 1 mg/kg/day (converted to 0.71 mg/kg/day based on intermittent exposure) for rats in a 12-week study (Bruckner et al. 1986 ERA 1989b IRIS 1993). The critical effect was liver toxicity. A chronic oral RfD of 7x10 mg/kg/day was also calculated based on the same NOAEL used for the subchronic RfD. The ATSDR has calculated an acute inhalation MRL of 0.2 ppm based on a LOAEL of 50 ppm for liver effects in an acute 4-day rat inhalation study (David et al. 1981), and an intermediate inhalation MRL of 0.05 ppm based on a NOAEL of 5 ppm for liver effects in an intermediate-duration (187-192 days) inhalation study in rats (Adams et al. 1952). The ATSDR has also calculated an acute oral MRL of 0.02 mg/kg/day based on a LOAEL of 5 mg/kg/day over 10 days for liver effects in the rat (Smialowicz et al. 1991), and an intermediate oral MRL of 0.007 mg/kg/day based on a NOAEL of 1 mg/kg/day over 12 weeks (converted to 0.71 mg/kg/day based on intermittent exposure) for liver effects in the rat (Bruckner et al. 1986). 

Due to the high doses necessary for acute effects as observed in short-term toxicity tests and to the lack of effects seen at earlier time-points in long-term studies, only chronic reference doses are used in conjunction with exposure for the calculation of triazine dietary risk. Therefore, the remainder of this discussion is limited to chronic exposure and risk. 

The most important factor is the dose-time relationship. The dose-time relationship forms the basis for distinguishing between two types of toxicity acute and chronic. Acute toxicity of a chemical refers to its ability to inflict systemic damage as a result (in most cases) of a one-time exposure to relative large amounts of the chemical. In most cases, the exposure is sudden and results in an emergency situation. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

In the prediction of long-term "no effect" doses there are two important concepts to consider. One is that there are predictable dose relationships between acute, subchronic and chronic toxic effects. Acute toxicity tests refers to studies wherein single or repeated doses are studied 14 days or less. Subchronic (subacute) tests refers to studies wherein the doses are given five-seven days per week for 90 days, Subchronlc studies are also referred to as 13-week, three-month or short-term tests. 

See also Benchmark Dose Exposure Assessment Exposure Criteria Hazard Identification Hormesis, LD50/ LC50 (Lethai Dosage 50/Lethai Concentration 50) Levels of Effect in Toxicoiogicai Assessment Maximum Allowable Concentration (MAC) Maximum Tolerated Dose (MTD) Pharmacokinetics/Toxicokinetics Reference Concentration (RfC) Reference Dose (RfD) Risk Assessment, Ecological Risk Assessment, Human Health Risk Characterization Toxicity, Acute. 

See also Acceptable Daily Intake (ADI) Dose-Response Relationship Reference Dose (RfD) Toxicity, Acute Toxicity, Chronic Uncertainty Factors. 

Molybdenum occurs naturally in various ores the principal source being molybdenite (MoS ). Molybdenum compounds are used primarily in the production of metal allo). Molybdenum is also considered an essential trace element with the provisional recommended dietary intake of 75-250 pg/day for adults and older children. There is no information available on the acute or subchronic oral toxicity of molybdenum in humans. Subchronic and chronic Reference Concentrations (RfC) for Mo are not available. Information on the inhalation toxicity of Mo in humans following acute and subchronic exposures is also not available. The chronic oral Reference Dose (RfD) for Mo and Mo compounds is 0.005 mg/kg/day, based on biochemical indices in humans. The subchronic RfD is also 0.005 mg/kg/day. Mo is placed in EPA Group D, not classifiable as to carcinogenicity in humans. ... 

RTECS Registry of Toxic Effects of Chemical Substances number is a unique and unchanging number used to cross-reference the RTECS database, which is a compendium of data extracted from the open scientific literature. Six types of toxicity data are included in each file (1) primary irritation, (2) mutagenic effects, (3) reproductive effects, (4) tumorigenic effects, (5) acute toxicity, and (6) other multiple dose toxicity. 

---