Chemical food additives, safe level

Historically, the so-called safety factor approach was introduced in the United States in the mid-1950s in response to the legislative needs in the area of the safety of chemical food additives (Lehman and Fitzhugh 1954). This approach proposed that a safe level of chemical food additives could be derived from a chronic NOAEL from animal studies divided by a 100-fold safety factor. The 100-fold safety factor as proposed by Lehman and Fitzhugh was based on a limited analysis of subchronic/chronic data on fluorine and arsenic in rats, dogs, and humans, and also on the assumption that the human population as a whole is heterogeneous. Initially, Lehman and Fitzhugh reasoned that the safety factor of 100 accounted for several areas of uncertainty ... 

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. 

The parent CDs as GRAS food additives are suitable for oral pharmaceutical use when used at the levels approved for foods. The GRAS estimated daily mean oral exposures for P-CD, a-CD, and y-CD were reported as 300, 1700, and 4000mg/day, respectively. These levels provide reasonable quantities for consideration in oral pharmaceutical products. As stated earlier, the parent CDs, however, are not suited for intravenous (TV) use due to the early reports of their renal toxicity, and this limitation led researchers to introduce chemical modifications to provide new, system-ically safe CDs for use in parenteral pharmaceuticals. 

The risk to health from chemicals in food can be assessed by comparing estimates of dietary exposure with recommended safe levels of exposure. For most metals and other elements, these are the Provisional Tolerable Weekly Intakes (PTWIs) and the Provisional Tolerable Daily Intakes (PTDIs) recommended by the Joint Expert Committee on Food Additives of the Food and Agricultural Organisation of the United Nations and the World Health Organisation International Programme on Chemical Safety (JECFA). The European Commission s Scientific Committee on Food has established other relevant safe levels. These are Acceptable Daily Intakes (ADIs) for chemicals added to food, and Tolerable Daily Intakes (TDIs) for chemical contaminants. The use of the term tolerable implies permissibility rather than acceptability. All the above recommendations are estimates of the amount of substance that can be ingested over a lifetime without appreciable risk, expressed on a daily or weekly basis as appropriate. 

EPA bases its procedures for estimating RfD on several assumptions, the most basic of which is that a threshold exists in the dose-response relationship for the critical response. If the dose is above the threshold (not the same as RfD) and is of sufficient duration, EPA considers that the chemical will cause the response in some segment of the exposed population. The U.S. Food and Drug Administration uses a similar approach to identify safe levels of exposure to food additives and certain residues. Studies on many substances have shown that before toxicity occurs, the chemical must deplete a physiological reserve or overcome the various repair capacities in the human body (Klaassen et al., 1996). 

GRAS A level of substance or chemical generally recognized as safe (the term refers to food additives and related substances). 

Most chemicals that are direct additives to drinking water present little hazard to health. Many of these chemicals also have been used as food additives and have been subjected to appropriate levels of toxicological testing. Other additives, such as starch, are natural foodstuffs and would be generally regarded as safe, especially at the low concentrations that would be expected to reach the tap. 

The task of assigning safe exposure levels for chemicals has traditionally been assigned to toxicologists. During the first half of this century, this problem arose in connection with food additives, pesticides, drugs, and occupational exposures. Although toxicologists experimented with a variety of... 

In 1954, the Food and Drug Administration published a paper that defined the basis for the acceptable daily intake (ADI). The ADI was a threshold for intake of a chemical for a large population, below which there should be no significant toxic risks. The paper not only defined a procedure for the ADI, but also described the use of safety factors and how animal data could be used to estimate risk to humans. A no effect level was determined from animal studies and a safety factor of 100 was used to establish a safe level. Tolerances for chemical additives and pesticides were calculated, comparing the safe level to the residue concentration of these chemicals in crops (e.g., wheat) and that crop s contribution to the individual s daily diet. 

The ability of toxicity testing to set safe levels is its most important practical function. The procedure has been developed most rigorously in the field of food and color additive testing -- chemicals added to foods -- where a series of special stipula-... 

For nongenotoxic chemicals, risk assessment is based on the concept of threshold doses, below which no adverse effect results from exposure. From human or experimental animal data, one tries to establish the no observable adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). In order to establish safe levels of exposure to potentially toxic agents, the NOAEL is divided by a safety factor (often named uncertainty factor). When the risk assessment is based on data from experimental animals, a default safety factor of 100 is usually applied. The safety factor constitutes a factor of 10 for potential differences in susceptibility between animals and man, and another factor of 10 for interindividual differences among humans. The factors are combinations of differences in toxicokinetics and toxicodynamics, both in animals and man. If true factors are known, the size of the safety factor may be changed accordingly. When risk assessment is based on human data, a safety factor of 10 is applied in most cases, for instance, for food additives. However, for natural toxins in food, smaller factors are usually applied. This is a risk management decision, often based on information on the absence of adverse health effects at intake levels close to the estimated LOAELs. 

Safety of food is a basic requirement of food quality. Food safety implies absence or acceptable and safe levels of contaminants, adulterants, naturally occurring toxins, or any other substance that may make food injurious to health on an acute or chronic basis. Most countries, therefore, have established official tolerance levels for chemical additives, residues, toxins, and contaminants in food products. Table 30.5 summarizes several CE reports that can be found in the literature that deal with the analysis of toxins, contaminants, pesticides, and residues. A number of reviews appearing... 

The objective of chemical safety testing is to prevent the introduction into the environment of chemicals that represent a significant health hazard to humans or to the immediate environment on which maintenance of the human species depends. For chemicals that must remain in the environment for one reason or another, safety testing can be used to establish a safe or tolerable exposure level. The potential benefit of test results from evaluations for genotoxicity applied to human health considerations can be substantiated by the early indications of genotoxic activity for vinyl chloride, tris-(2,3-dibromo-propyl) phosphate (TRIS), benzene, hycanthone, and the Japanese food additive 2-(2-furyl)-3-(5-nitrofuryl)acrylamide(AF-2). In some of these cases, mutagenic data were available before the chemicals were identified as animal carcinogens. 

US Food and Drugs Administration, FDA, the World Health Organization, WHO, and the European Commission s Scientific Committee on Food, SCF, must confirm that ingestion of all additives remains within safe levels. It applies to people of all ages, children as well as adults. Health consumer protection in Germany (Bundesinstitut, BgW) also examines poisonous effect of chemicals present in commercial products. 

In 1958, in response to the increased awareness that chemicals can cause cancer, the US Congress passed the Delaney clause, which prohibited the addition to the food supply of any substance known to cause cancer in animals or humans. Compared with today s standards, the analytical methods to detect a potentially harmful substance were very poor. As the analytical methods improved, it became apparent that the food supply had low levels of substances that were known to cause cancer in either animals or humans. The obvious question was Is a small amount of a substance safe to consume. This question in turn raised many others about how to interpret data or extrapolate data to very low doses. The 1970s saw a flourishing of activity to develop and refine risk assessment methodologies. 

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