Dose-Response Concepts

1 Dose-response concepts. Dose-response assessment for hazardous chemicals that can cause deterministic effects begins with the toxicology data developed during the hazard identification step described in Section 3.1.4.1.2. In many cases, hazard identification and dose-response assessment occur simultaneously. For each chemical, the critical response (a specific response in a specific organ) is identified in the hazard identification process. Using the available data for the critical response, one of the following is established  

NOAEL (or LOAEL if NOAEL is not available) is used as a point of departure to calculate a reference dose (RfD), which is the highest dose of the chemical at which no statistically significant adverse effects are expected in the most sensitive humans. RfD of a particular substance is calculated from NOAEL (or LOAEL) by applying one or more safety and uncertainty factors. RfD usually is 100 to 1,000 times lower than NOAEL or 1,000 to 10,000 times lower than 

2 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). 

LOWEST OBSERVED ADVERSE EFFECT LEVEL (LOAEL) 

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). 

---

Kane, A.S., Dose response concepts, Applied Toxicology NURS 735—Module 1, http //aquaticpath. umd.edu/appliedtox/dose-response.pdf... 

Since the second edition appeared, much of the interest in soil chemistry has been on the fate of so-called toxic chemicals and elements in soils. This edition points out that (1) all of the chemical elements—toxic and beneficial—were always in the soil, (2) the soil is the safest part of the environment in which to deposit our wastes, (3) there are wise and unwise ways to utilize soil for waste disposal, (4) soil chemistry degrades wastes and converts them into benign or useful substances, (5) environmental activists and the popular media usually ignore the dose-response concept that is central to toxicology and to soil fertility, and (6) how much is in the soil, how fast it is changing, and how easily it transfers to plants and water are more important than what is there. Soil chemistry can answer those important questions. A goal for the future is to answer them better. 

These examples of theory limitations and others led to modification in the receptor-based dose response concept during the middle decades of the twentieth century. Most notably was that of Ariens at the University of Nijmegan in The Netherlands, who proposed that the drug-receptor union may have varying effectiveness, which he called intrinsic activity, and which Stephenson referred to as efficacy. This efficacy or intrinsic activity concept became expressed in quantitative terms as the rate constant of the second step of a drug-receptor process that yielded the active form of the receptor. 

Despite the strong identification of this concept with Schulz, numerous independent researchers such as Jensen commonly observed this dose-response relationship, often without any apparent knowledge that this biphasic dose-response was actually part of a controversial dose response concept of Schulz. Other investigators created a journal called Cell Stimulation based upon the Arndt-Schulz Law/hormesis concept. However, after what appeared to be a very successful initial six years, the publication was ceased in 1930 for reasons that are unclear. 

The aroma of fmit, the taste of candy, and the texture of bread are examples of flavor perception. In each case, physical and chemical stmctures ia these foods stimulate receptors ia the nose and mouth. Impulses from these receptors are then processed iato perceptions of flavor by the brain. Attention, emotion, memory, cognition, and other brain functions combine with these perceptions to cause behavior, eg, a sense of pleasure, a memory, an idea, a fantasy, a purchase. These are psychological processes and as such have all the complexities of the human mind. Flavor characterization attempts to define what causes flavor and to determine if human response to flavor can be predicted. The ways ia which simple flavor active substances, flavorants, produce perceptions are described both ia terms of the physiology, ie, transduction, and psychophysics, ie, dose-response relationships, of flavor (1,2). Progress has been made ia understanding how perceptions of simple flavorants are processed iato hedonic behavior, ie, degree of liking, or concept formation, eg, crispy or umami (savory) (3,4). However, it is unclear how complex mixtures of flavorants are perceived or what behavior they cause. Flavor characterization involves the chemical measurement of iadividual flavorants and the use of sensory tests to determine their impact on behavior. 

Dose-response relationship 1 he toxicological concept that the toxicity of a substance depends not only on its toxic properties, but also on the amount of exposure or dose. 

The LCjj concept is visualized in the dose-response curve presented in Figure 4-114 [32A]. The dose or concentration is plotted on the abscissa, and... 

The concept of dose response in pharmacology has been known and discussed for some time. A prescription written in 1562 for hyoscyamus and opium for sleep clearly states, If you want him to sleep less, give him less [13], It was recognized by one of the earliest physicians, Paracelsus (1493-1541), that it is only the dose that makes something beneficial or harmful All things are poison, and nothing is without poison. The Dosis alone makes a thing not poison. ... 

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

A recent series of experiments which may be related to this concept has been reported by Prehn and Lawler (29) They treated 10 strains of mice with two different dose levels (5% and 0.05%) of 3-methylcholanthrene and observed that the rank order of susceptibility, as measured by the average number of tumor-free days, was reversed on going from the higher to the lower dose. They suggested differential stimulation of immune response as an explanation of their results but it is also possible that different dose-responses, as suggested by Druckrey s equation (equation 5), may be important. 

Studies in rodents, dogs, and non-human primates have demonstrated all of the major types of health effects of lead that have been observed in humans, including cardiovascular, hematological, neurodevelopmental, and renal effects (EPA 1986a). These studies also provide support for the concept of blood lead concentration as a metric of internal dose for use in dose-response assessments in humans. 

Our assignment for EPA was to apply quantitative risk analysis methods to the determination of risk for a particular chemical. The health risks for perchloroethylene turned out to be highly uncertain, but by using decision analysis concepts we were able to display this uncertainty in terms of alternative assumptions about the dose response relationship. Similar methods might be used to characterize uncertainties about human exposure to a chemical agent or about the costs to producers and consumers of a restriction on chemical use. 

As an alternative to the traditional NOAEL approach, the BMD concept has been proposed for use in the quantitative assessment of the dose-response relationship, see the next section. 

The concept of the Benchmark Dose (BMD), a benchmark is a point of reference for a measurement, in health risk assessment of chemicals was first mentioned by Crump (1984) as an alternative to the NOAEL and LOAEL for noncancer health effects in the derivation of the ADI/TDI these terms are addressed in detail in Chapter 5. The BMD approach provides a more quantitative alternative to the dose-response assessment than the NOAEL/LOAEL approach. The goal of the BMD approach is to define a starting point of depariure (POD) for the establishment of a tolerable exposure level (e.g., ADI/TDI) that is more independent of the study design. In this respect, the BMD approach is not... 

The concept of categorizing carcinogens into threshold carcinogens and non-threshold carcinogens is a pragmatic approach that simplifies the reality of dose-response relationships. The observed dose-response curve for tumor formation in some cases represents a single rate-determining step however, in many cases it may be more complex and represent a superposition of a number of dose-response curves for the various steps involved in the mmor formation. It is therefore more realistic to assume that there is a continuum of shapes of dose-response relationships which cannot be easily differentiated by data and information usually available. 

In Phase 2 the studies are conducted to prove the therapeutic concept and evaluate efficacy and assure that measures of efficacy are adequate. Importantly, dose-response studies are conducted to determine the therapeutically useful dose range and to establish doses to be used in full-scale clinical trials. These studies are closely monitored and well controlled in a small to moderate numbers of patients with the condition of interest. Study results may also give some idea of common dose-related adverse events following short-term therapy. 

An immunologic basis for chronic beryllium disease has been postulated and a hypersensitivity phenomenon demonstrated. Consistent with the concept of chronic berylliosis as a hypersensitivity pulmonary reaction are the following Persons with berylliosis also show delayed cutaneous hypersensitivity reactions to beryllium compounds their peripheral blood lymphocytes undergo blast transformation and release of macrophage inhibition factor after exposure to beryllium in vitro helper/suppressor T-cell ratios are depressed and there is lack of a dose-response relationship in chronic beryllium cases. Hypersensitization may lead to berylliosis in people with relatively low exposures, whereas nonsensitized individuals with higher exposures may have no effects. 

A characteristic feature of allelopathy is that the inhibitory effects of allelopathic compounds are concentration dependent. Dose-response curves with known compounds show an inhibition threshold. Below this level either no measurable effect occurs, or stimulation may result. Although the concentration of a compound required to exceed the inhibition threshold varies extensively according to different sensitivities among species and also among phases of the growth cycle for higher plants, the concept of an inhibition threshold seems consistent. Thus, it is reasonable to evaluate how, and if, a subthreshold concentration of an allelochemical may contribute to allelopathic interference. Also in need of evaluation is how environmental conditions may influence the deleterious action of an allelochemical and the concentration required for an effect. Such interactions are especially pertinent for those environmental situations that place some degree of stress on plant functions. 

To ensure the health and well-being of our children and all life we must protect the genetic potential of the individual. Even a low level of lead exposure during childhood may rob the child of its genetic potential. The concept of dose-response must be expanded to include the sensitive individual and protecting genetic potential. 

---