Threshold of toxicity

For oral exposures, different fuel oils have differing lethality profiles in rats. Acute lethal doses in rats were reported to be 12,000 mg/kg for kerosene (Muralidhara et al. 1982) and 47,300 mg/kg for JP-5 (Parker et al. 1981). However, an oral dose of 12,200 mg/kg of Deobase was not lethal in rats (Muralidhara et al. 1982). Although differences in the oral toxicity of fuel oils and differences in species thresholds of toxicity may exist, the oral toxicity of fuel oils is relatively low. The intestinal absorption of fuel oils is also relatively low, and aspiration, with its resultant pulmonary effects, is the primary risk from the ingestion of fuel oils. 

Safety factor approach for chemicals that cause deterministic effects. Traditional toxicologic procedures for chemicals that can induce deterministic effects, which are assumed to have a threshold dose, define RfD for humans or animals as some fraction of NOAEL. This fraction is determined by establishing safety factors to account for weaknesses and uncertainties in the data and in the extrapolation from animals to humans. In the safety factor approach, doses below RfD are assumed not to result in a response because they are below the threshold of toxicity (Dourson and Stara, 1983 Renwick and Lazarus, 1998 Weil, 1972). 

Hanson ML, Solomon KR. 2002. New technique for estimating thresholds of toxicity in ecological risk assessment. Environ Sci Technol 36 3257-3264. 

An evaluation of the dose-response characteristics of chemicals is at the heart of the problem of understanding the health risks they may pose. If for every chemical in the environment we knew the range of no-effect doses and the point at which toxicity begins to appear — the point at which the threshold of toxicity is passed - we could then act to prevent exposures from ever reaching the level at which harmful doses are created (the reader may briefly review Chapter 2 for a discussion of... 

Traditional cancer risk assessment has taken a different approach. As a defanlt assumption, carcinogens have been considered to act withont a threshold of toxicity... 

B. Euthyroid persons and children appear to have a high tolerance to the effects of an acute overdose. Patients with preexisting cardiac disease and those with chronic overmedication have a lower threshold of toxicity. Sudden deaths have been reported after chronic thyroid hormone abuse in healthy adults. 

SCF opinion on the scientific basis of the concept (requested by the EU Commission), published on 8 March 1996, found it a sound concept, but requested an up-to-date review covering more end-points than carcinogenicity, and possibly two Thresholds (non-genotoxic and genotoxic substances). It also noted that the FDA risk assessment process is different from Europe. APME formed a Task Force with the chemicals industry body CEFIC-FCA in 1995 to evaluate a regulatory concept. ILSI (the International Life Science Institute) formed a Task Force on Threshold of Toxicity in 1996. 

Preclinical studies must be performed before an ingredient can be considered for clinical studies in humans in order to determine the potential toxicity of the ingredient and its metabolites and their effects in the matrix. Preclinical studies allow researchers to expose cell cultures and experimental animals to doses of ingredients not normally encountered in human consumption. Results of such assessments are used to determine the threshold of toxicity for the given ingredient (i.e., the margin of safety). 

A toxicity threshold is typically estimated from a short-term toxicity study on a single chemical with a clearly defined toxic endpoint. Estimating a threshold dose— indeed, investigating whether a threshold exists—is more difficult when exposure is to low doses of a chemical over long periods of time. As a rule, the number of animals required to identify a toxicity threshold in long-term, low-dose studies is prohibitively expensive, and snch studies are rarely, if ever, performed. The question of toxicity thresholds is complicated further because real-world exposures are typically not to one chemical, bnt to multiple chemicals in changing combinations over time. More studies are needed to characterize thresholds of toxicity both for single chemicals and chemical mixtnres. 

Discuss the concept of threshold in chemical toxicity. How is the no observed adverse effect level (NOAEL) determined What is the relationship of the NOAEL to the threshold of toxicity ... 

The threshold is the dose of a chemical below which a toxic effect does not occnr and above which the toxic effect occnrs with increasing frequency as the dose is increased. The threshold dose cannot be measured directly because it does not itself canse the toxic effect. The NOAEL is the dose that canses the toxic effect in enongh animals to be observed bnt in too few to achieve statistical signihcance. The NOAEL is not a trne threshold of toxicity rather, it lies above the threshold. Approximately 5% to 10% of animals are affected by the NOAEL, presnmably the most sensitive individuals in the test popnlation. 

Despite the high levels of surficial sedin nt contamination by PAH compounds in Sinclair Inlet found in this study, the san5>ling and analysis technique reported here revealed relatively low PAH concentrations in the unfiltered water samples collected from above these sediments. Reported thresholds of toxicity to aquatic organisms typically exceed the water concentrations measured here by at least three orders-of-magnitude (7). 

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