Chronic reference concentration

EPA has developed a chronic reference concentration (RfC) for chronic exposure of 80 mg/m3 (Integrated Risk Information System (IRIS) 1998), based primarily on a 2-year inhalation study in rats (Collins et al. 1995). Briefly, male rats exposed at concentrations of 10,000 ppm and 50,000 ppm had a significant increase in the incidence of Leydig cell hyperplasia compared with controls. The study is described below. 

The US EPA has developed a chronic reference concentration (RfC) of 2xl0 mgm ( 0.0014 ppm) based on a critical effect of nasal... 

Chronic Reference Concentration (RFC) RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure for a chronic duration (up to a lifetime) to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL, lowest observed adverse effect level (LOAEL), or benchmark concentration, with uncertainty factors generally applied to reflect limitations of the data used. 

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. ... 

EPA s Integrated Risk Information System (IRIS) lists an oral reference dose (RfD) of 0.006 mg/kg/day for endosulfan (IRIS 2000). No reference concentration (RfC) for chronic inhalation exposures to endosulfan was reported. 

EPA has derived both an oral reference dose (RfD) and an inhalation reference concentration (RfC) for chronic exposure to hydrogen sulfide. The RfD of 0.003 mg/kg/day is based on the NOAEL of 3.1 mg/kg/day for gastrointestinal disturbance in pigs in a study by Wetterau et al. (1964) (IRIS 1998). The NOAEL value of 3.1 mg/kg/day was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation (10), sensitive individuals (10), and subchronic exposure (10) (IRIS 1998). 

ATSDR has derived a chronic oral MRL of 0.0003 mg/kg/day based on a laboratory animal study showing neurotoxic effects in dogs (Kettering Lab 1969). The EPA reference dose for endrin is 3xl0 4 mg/kg/day, and the critical dose is 0.025 mg/kg/day (IRIS 1995). Critical effects were occasional convulsions and mild histological lesions in the liver (Kettering Lab 1969). No EPA reference concentration exists for the compound. 

Table 7-2 lists some of the more common solvents, along with some of their effects and their hazard potential. The word acute in the table refers to a short-term, relatively high concentration exposure, while the term chronic refers to a long-term, relatively low exposure. The column labeled Hazard Potential gives the recommended exposure limit. A question mark after a comment indicates that there is some doubt about the conclusion. 

Oral reference doses and inhalation reference concentrations (RfDs and RfCs, respectively) for chronic noncarcinogenic health effects... 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

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. 

The RfC (reference concentration) method for chronic exposure to gases was proposed by EPA (1994) as an approach to the dosimetry correction for effects on the respiratory system. This method has not been used by the NAC/ AEGL Committee for the following reasons (1) the RfC dosimetry corrections from animal to man are based on theoretical constructs that have not been confirmed and validated with experimental data (2) some of the RfC assumptions are qnestionable and can have a significant impact upon the calculated dosimetry correction between animals and humans. Below is a discussion of two key examples and their impact upon the dosimetry adjustment. The assnmptions are the requirement of uniform deposition in compartments and eqnivalent percent of deposition in animals and humans. 

Interspecies and intraspecies UFs have been used in the development of safe or threshold exposure levels for chronic, noncancer toxicity by health organizations throughout the world. Examples include the acceptable daily intake (ADI) (Lu 1988 Truhaut 1991 Lu and Sielken 1991), the tolerable daily intake (TDI) or tolerable concentration (TC) (Meek et al. 1994 IPCS 1994), the minimal risk level (MRL) (Pohl and Abadin 1995), the reference dose (RfD) (Barnes and Dourson 1988 Dourson 1996), and the reference concentration (RfC) (EPA 1994 Jarabek et al. 1990). The importance of using distribution-based analyses to assess the degree of variability and uncertainty in risk assessments has been emphasized in recent trends in risk analysis. This will enable risk managers to make more informed decisions and... 

Chronic exposure to 1,1,1-trichloroethane has resulted in some liver damage and neurological effects in experimental animals. US Environmental Protection Agency (EPA) has not established a reference concentration (RfC) or a reference dose (RfD) for this material. 

House dust serves as a reservoir for pesticides in households [85]. Dust ingestion scenarios show that exposures could also exceed the diazinon chronic reference dose [115]. Support for the thesis that household dust may not only be a direct exposure path but may serve as an indicator for all indoor exposure paths can be concluded from correlations between pesticides in dust and in samples of human origin. Regarding PCP, a semivolatile pesticide, concentrations in urine of women and children corresponded well with indoor dust samples from vacuum cleaner bags [13,136]. 

CHRONIC HEALTH RISKS probable human carcinogen implicated as brain carcinogen mutation data reported may cause genetic damage no information available on reproductive or developmental effect on humans EPA has not established a reference concentration due to inadequate data reference dose not established by EPA. 

Poisons can be acute (with immediate effect, e.g., hydrogen cyanide (HCN)) or chronic (referring to the systemic damage done after repeated exposure to low concentrations over long periods of time, e.g., heavy metals like mercury, lead, cadmium and also vinyl chloride). The chemicals most often associated with chronic toxicity are also carcinogens (e.g., benzene, cadmium compounds), which are problematic because when, if at all, the... 

Toxicity Data on Af- Vinyl-2-Pyrrolidinone. Results of a chronic inhalation study in rats warrant a review of industrial hygiene practices to assure that VP vapor concentrations are maintained at a safe level. One of the manufacturers, ISP, recommends that an appropriate workplace exposure limit be set at 0.1 ppm (vapor) (9). Additionally, normal hygienic practices and precautions are recommended, such as prompt removal from skin and avoidance of ingestion. In case of accidental eye contact, immediately flush with water for at least 15 minutes and seek medical attention. Refer to the manufacturers Material Safety Data Sheets for more detailed information. Table 3 provides some toxicity data. 

TBW depletion (often referred to as dehydration ) is typically a more gradual, chronic problem compared to ECF depletion. Because TBW depletion represents a loss of hypotonic fluid (proportionally more water is lost than sodium) from all body compartments, a primary disturbance of osmolality is usually seen. The signs and symptoms of TBW depletion include CNS disturbances (mental status changes, seizures, and coma), excessive thirst, dry mucous membranes, decreased skin turgor, elevated serum sodium, increased plasma osmolality, concentrated urine, and acute weight loss. Common causes of TBW depletion include insufficient oral intake, excessive insensible losses, diabetes insipidus, excessive osmotic diuresis, and impaired renal concentrating mechanisms. Long-term care residents are frequently admitted to the acute care hospital with TBW depletion secondary to lack of adequate oral intake, often with concurrent excessive insensible losses. 

The Critical concentrations with respect to the soil organisms should be related to a low effect level on the most sensitive species. The effects on the process of metabolism and other processes within the organisms should be considered and also the diversity of the species, which is most sensitive to the heavy metals, has to be accounted. Critical limits must refer to the chronic or accumulated effects. For assessment of the critical concentrations in crops and in drinking water, human-toxicological information is required. In general, for establishing critical loads we should also account the additive effects of the different metals and combination effect between the acidification and biogeochemical mobilization of the heavy metals in soils and bottom sediments. 

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