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TERMINOLOGY AND BASIC SCIENTIFIC FACTS The Fluoride Report Issue #9 Regarding fluoride, if it is an essential trace element, then there should be an optimal dose that will have a beneficial effect on health, including dental health, and an excessive dose that will become toxic. This leads us to elaborate on the terminology and on some basic scientific facts that are not often addressed in the debate. The voluminous U.S. National Research Council report, Fluoride in Drinking Water, a Scientific Review of EPA's Standards , published in 2006 is the most serious analysis of fluoride intake in the United States as it calculates risk factors. ​ DOSE-RESPONSE OR DOSE-EFFECT RELATIONSHIP We talk about dose-response or dose-effect relationship or even exposure-response relationship, to refer to the effects of a dose of an active substance, be it a trace element, on an individual or on a group of people. The dose-response or dose-effect relationship depends on several factors, such as age, weight, state of health or nutrition, the presence of other toxic substances, the type of substance and the duration of exposure. The substance can be medicinal in nature, but also chemical, natural or toxic. The timing of exposure in the life cycle may also be important because some products may have no effect on an adult individual but may be more beneficial (as is believed for fluoride during tooth formation), but be deleterious to an embryo or a young baby. The dose-response relationship must be studied from all angles to understand the action of a substance in terms of health. The dose-effect relationship or exposure-response relationship or more simply written dose-response expresses the change of effects on an organism, caused by a different quantity of the active substance after a certain time of exposure. It can apply to individuals, for example, where a small amount has no effect, a larger dose can be fatal. In a population, a number of individuals may be affected while the majority will not. Pharmacokinetic and toxicology studies help to understand the mechanisms of action of the substance and the target tissues that will be affected. The concept of dose-response relationship is therefore at the heart of scientific studies on nutrients, trace elements, toxic substances and contaminants. TOXIC THRESHOLD The concept of a toxic threshold is important for a nutrient because it serves to set standards for the optimal amount for the maintenance of health and for the amount at the upper limit that will become toxic. The threshold value represents the minimum quantity below which no toxic effect occurs. Above this threshold, the observed effect will be dose-dependent. This threshold is explained by the fact that the human body is made up of a large number of types of cells, tissues and organs with varying sensitivity, some being more sensitive to certain substances than others. In addition, the body has mechanisms of defense, excretion or adaptation. These mechanisms consequently monopolize a part of its energy to achieve these. The same principle applies to a population of individuals, because the effect or many possible harmful effects can manifest themselves differently from one person to another, despite being exposed to the same dose of a nutrient or a poisonous substance. NO OBSERVABLE ADVERSE EFFECT LEVEL (NOAEL) From these concepts of toxicology, an associated terminology has been developed. Among the most important, we must speak of the No Observable Adverse Effect Level (NOAEL), also called level without toxic effect, maximum dose without effect or maximum dose without observable adverse effect. It is defined as the highest dose of a substance producing no observable harmful effects during a toxicity study. This unit of measurement is used more particularly in the field of low doses, therefore very applicable for fluoride. TOLERABLE UPPER INTAKE LEVELS (ULS) The Tolerable Upper Intake Levels (ULs) are the maximum levels that can be consumed daily on a chronic basis without adverse effects. The Tolerable Upper Intake Levels will generally be much lower than the levels that would cause adverse effects. It is also recommended that the Tolerable Upper Intake Levels be used as the reference exposure level for human health risk assessment. It is the term published by the Institute of Medicine of the National Academies (IOM). TOXICOLOGICAL REFERENCE VALUE (TRV) The Toxicological Reference Value (TRV) is a toxicological index making it possible, by comparison with exposure, to qualify or quantify a risk to human health. The method of establishing TRVs depends upon the data available on the mechanisms of toxicological action of the substances and commonly accepted assumptions. In the case of fluoride toxicity, moderate dental fluorosis could be taken as the minimal index of its toxicity, whereas it may well not be the most sensitive index despite being the most commonly accepted. Toxicological Reference Values are widely used in the quantitative health risk assessment process, a decision-making process aimed at providing the essential scientific elements of a proposal or recommendation. REFERENCE DOSE (RfD) Another term closely related to the Toxicological Reference Value (TRV) is the Reference Dose (RfD), which aims to adequately protect infants and children but which, generally, has not been considered for embryos. It is defined as an estimate of the daily exposure for a human population (including the most sensitive subgroups) that would probably be without appreciable risk of deleterious effects over a lifetime. ACCEPTABLE DAILY INTAKE (ADI) or TOLERABLE DAILY INTAKE (TDI) The Acceptable Daily Intake (ADI) or Tolerable Daily Intake (TDI) is the amount of a substance that an individual should be able to ingest each day, without risk to health. It is usually expressed in mg of substance per kg of body weight per day (mg/kg/day). It should be understood here that the maximum daily dose is proportional to the weight of the individual. The maximum dose is therefore, in fact, much lower for an infant than for an adult individual. RECOMMENDED DAILY ALLOWANCES (RDA) The Recommended Daily Allowances (RDA) are benchmark values for the quantity of micronutrients (vitamins and minerals) necessary for the health of an average adult. They are used as a reference for the labeling of food products. The terms Nutritional Reference Values (NRVs), Reference Intakes, or Daily Reference Intakes may replace the term Recommended Daily Allowances or RDA. RECOMMENDED DAILY DOSE The Recommended Daily Dose also comes back to this same concept in relation to a nutritional supplement or a drug and it will generally be adjusted according to the weight and age of the subject according to a dose scale. SAFETY FACTOR (SF) This concept grants a margin of safety, generally 10, particularly essential when the variables involved are numerous (age, weight, nutritional status, state of health, environment) and when the sources of intake of the substance studied are multiple and variable, depending on the individual, in their potential for quantitative contribution and over time. DESCRIPTION OF THE TRADITIONAL APPROACH In many cases, risk decisions on systemic toxicity have been made using the concept of the Acceptable Daily Intake (ADI) derived from an experimentally determined No Observed Adverse Effect Level (NOAEL). The ADI is commonly defined as the amount of a chemical to which a person can be exposed on a daily basis over an extended period of time (usually a lifetime) without suffering a deleterious effect. The ADI concept has often been used as a tool in reaching risk management decisions (e.g., establishing allowable levels of contaminants in foodstuffs and water.) A NOAEL is an experimentally determined dose at which there was no statistically or biologically significant indication of the toxic effect of concern. In an experiment with several NOAELs, the regulatory focus is normally on the highest one, leading to the common usage of the term NOAEL as the highest experimentally determined dose without a statistically or biologically significant adverse effect. The NOAEL for the critical toxic effect is sometimes referred to simply as the NOEL. This usage, however, invites ambiguity in that there may be observable effects that are not of toxicological significance (i.e., they are not "adverse"). For the sake of precision, this document uses the term NOAEL to mean the highest NOAEL in an experiment. In cases in which a NOAEL has not been demonstrated experimentally, the term Lowest Observed Adverse Effect Level (LOAEL) is used. Once the critical study demonstrating the toxic effect of concern has been identified, the selection of the NOAEL results from an objective examination of the data available on the chemical in question. The ADI is then derived by dividing the appropriate NOAEL by a Safety Factor (SF), as follows: ADI (human dose) = NOAEL (experimental dose)/SF. (Equation 1) Generally, the SF consists of multiples of 10, each factor representing a specific area of uncertainty inherent in the available data. For example, a factor of 10 may be introduced to account for the possible differences in responsiveness between humans and animals in prolonged exposure studies. A second factor of 10 may be used to account for variation in susceptibility among individuals in the human population. The resultant SF of 100 has been judged to be appropriate for many chemicals. For other chemicals, with databases that are less complete (for example, those for which only the results of sub-chronic studies are available), an additional factor of 10 (leading to a SF of 1000) might be judged to be more appropriate. For certain other chemicals, based on well-characterized responses in sensitive humans (as in the effect of fluoride on human teeth) , an SF as small as 1 might be selected. While the original selection of SFs appear to have been rather arbitrary (Lehman and Fitzhugh, 1954), subsequent analysis of data (Dourson and Stara, 1983) lends theoretical (and in some instances experimental) support for their selection. Further, some scientists, but not all within the EPA, interpret the absence of widespread effects in the exposed human populations as evidence of the adequacy of the SFs traditionally employed.