Dose-response relationship assumptions

The law of mass action has been successfully applied to many drug dose-response relationships since the early work of Clark. The systematic relation between the dose of a drug and the magnitude of its response is based on three assumptions (1) response is proportional to the level of receptor occupancy (occupancy theory), (2) one drug molecule combines with one receptor site, and (3) a negligible fraction of total drug is combined with the receptors. These assumptions must also apply to Beidler s equation. 

Decision Analysis. An alternative to making assumptions that select single estimates and suppress uncertainties is to use decision analysis methods, which make the uncertainties explicit in risk assessment and risk evaluation. Judgmental probabilities can be used to characterize uncertainties in the dose response relationship, the extent of human exposure, and the economic costs associated with control policies. Decision analysis provides a conceptual framework to separate the questions of information, what will happen as a consequence of control policy choice, from value judgments on how much conservatism is appropriate in decisions involving human health. 

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. 

Since risk analysis plays an important role in public policy decision making, efforts have been made to devise a means by which to identify, control, and communicate the risks imposed by agricultural biotechnology. A paradigm of environmental risk assessment was first introduced in the United States by Peterson and Arntzen in 2004. In this risk assessment, a number of assumptions and uncertainties were considered and presented. These include (1) problem formulation, (2) hazard identihcation, (3) dose-response relationships, (4) exposure assessment, and (5) risk characterization. Risk assessment of plant-made pharmaceuticals must be reviewed on a case-by-case basis because the plants used to produce proteins each have different risks associated with them. Many plant-derived biopharmaceuticals will challenge our ability to define an environmental hazard (Howard and Donnelly, 2004). For example, the expression of a bovine-specihc antigen produced in a potato plant and used orally in veterinary medicine would have a dramatically different set of criteria for assessment of risk than, as another example, the expression of a neutralizing nonspecihc oral antibody developed in maize to suppress Campylobacter jejuni in chickens (Peterson and Arntzen, 2004 Kirk et al., 2005). 

A weight of evidence approach to assessing reproductive toxicity requires rigorous evaluation of all available data. However, often only limited information is available, and default assumptions must be made because of uncertainties in understanding mechanisms, dose-response relationships at low dose levels and human exposure patterns. Several of these assumptions are basic to the extrapolation of toxicity data from animals to humans, while others are specific to reproductive toxicity. The general default assumptions for reproductive toxicity stated in the IPCS (1995) report are summarized as follows ... 

The dose-response relationship is predicated on certain assumptions, however ... 

Toxicity shows a dose-response relationship and may range from subtle biochemical changes to lethality and may involve receptor interactions. The dose-response relation depends on certain assumptions the toxic response is a function of the concentration at the target site, the concentration at the target site is a function of dose, the toxic response is causally related to the compound. 

On what assumptions is the dose-response relationship predicated ... 

In section 2.3 of this chapter the present approach to characterisation of dose-response relationships was described. In most cases it is necessary to extrapolate from animal species that are used in testing to humans. It may also be necessary to extrapolate from experimental conditions to real human exposures. At the present time default assumptions (which are assumed to be conservative) are applied to convert experimental data into predictive human risk assessments. However, the rates at which a particular substance is adsorbed, distributed, metabolised and excreted can vary considerably between animal species and this can introduce considerable uncertainties into the risk assessment process. The aim of PB-PK models is to quantify these differences as far as possible and so to be able to make more reliable extrapolations. 

The doses of hazardous substances at which responses can be observed in humans or animals are higher (sometimes by large factors) than doses relevant to waste disposal and other routine exposure situations. Therefore, most dose-response relationships at the low doses of interest in protection of human health are calculated rather than measured they are based not only on scientific data but also on various assumptions and extrapolation models which, while scientifically plausible, cannot yet be subjected to empirical study... 

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). 

The acceptable risks for substances that induce stochastic responses discussed in this Section are values in excess of unavoidable risks from exposure to the undisturbed background of naturally occurring agents that cause stochastic responses, such as many sources of natural background radiation and carcinogenic compounds produced by plants that are consumed by humans. This distinction is based on the assumption of a linear, nonthreshold dose-response relationship for substances that cause stochastic responses and the inability to control many sources of exposure. Risk management can address exposures to naturally occurring substances that induce stochastic responses, but only when exposures are enhanced by human activities or can be reduced by reasonable means. 

In contrast, risk management for substances that cause deterministic effects must consider unavoidable exposures to the background of naturally occurring substances that cause such effects. Based on the assumption of a threshold dose-response relationship, the risk from man-made sources is not independent of the risk from undisturbed natural sources, and the total dose from all sources must be considered in evaluating deterministic risks. In the case of ionizing radiation, thresholds for deterministic responses are well above average doses from natural background radiation (see Section 3.2.2.1)... 

Establishing Allowable Doses of Substances That Cause Deterministic Responses. The risk index for substances that cause deterministic responses normally should be expressed in terms of dose, rather than risk, given the assumption of a threshold dose-response relationship. The allowable dose of substances that cause deterministic responses in the denominator in Equation 6.3 should be related to thresholds for induction of deterministic responses in different organs or tissues. 

Establishing Allowable Risks or Doses of Substances That Cause Stochastic Responses. Given the assumption of a linear dose-response relationship for substances that cause stochastic responses without threshold, either risk or dose may be used to calculate the risk index. The following two sections discuss suitable approaches to establishing negligible and acceptable risks or doses of substances that cause stochastic responses. 

Risk Index for Multiple Substances That Cause Stochastic Responses. The risk index for mixtures of substances that cause stochastic responses (radionuclides and chemicals) is based on an assumption of a linear, nonthreshold dose-response relationship. This risk index takes into account the stochastic risk in all organs or tissues, and it assumes that the risk in any organ is independent of risks in any other organs. Based on these conditions, and expressing the risk index for a single hazardous substance in terms of dose (see Equation 6.3), the risk index for mixtures of substances that cause stochastic responses, denoted by RIS, can be expressed as ... 

By examination of the organ-specific ratios of calculated doses to allowable doses obtained in the previous step, the maximum value of these ratios is selected. Application of the MAX function to these organ-specific ratios is based on an assumption that induction of deterministic responses in any organ is independent of doses in any other organs or, equivalently, that the threshold in the dose-response relationship for any substance that causes deterministic responses is not affected by exposure to multiple... 

If the risk index for all substances that cause deterministic responses in the waste (RId) in Equation 6.5 is zero (i.e., the doses of all substances that cause deterministic responses are less than the allowable values), classification is determined solely by the risk index for all substances that cause stochastic responses (RP) in Equation 6.4 the latter must be nonzero based on the assumption of a linear, nonthreshold dose-response relationship. On the other hand, if the risk index for all substances that cause deterministic responses is unity or greater, the calculated risk exceeds the allowable risk for the waste class of concern without the need to consider the risk posed by substances that cause stochastic effects. The only advantage of the form of the composite risk index in Equation 6.6 is that it indicates more explicitly that the total risk posed by a given waste is the sum of the risks posed by the two types of hazardous constituents, however approximate that representation may be. 

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