Background incidences

For all agents of concern in occupational toxicology (except therapeutics), the major route by which the general population is most frequently exposed is the percutaneous (dermal) route. Brown (1980) has previously reviewed background incidence data on pesticides, for example, that show such exposures to be common. Dermal (or topical) drugs are not as common, but are certainly numerous. 

TABLE 22.8. Average Number of Animals Needed to Detect a Significant Increase in the Incidence of an Event (tumors, anomalies, etc.) over the Background Incidence (control) at Several Expected Incidence Levels Using the Fisher Exact Probability Test (p = 0.05)... 

This model assumes that any dosage effect has the same mechanism as that which causes the background incidence. Low-dose linearity follows directly from this additive assumption, provided that any fraction of the background effect is additive no matter how small. A best fit curve is fitted to the data obtained from a long-term rodent cancer bioassay using computer programs. The estimates of the parameters in the polynomial are called Maximum Likelihood Estimates (MLE), based upon the statistical procedure used for fitting the curve, and can be considered as best fit estimates. Provided the fit of the model is satisfactory, the estimates of these parameters are used to extrapolate to low-dose exposures. 

For linear extrapolation, a line is drawn from the POD (from observed data), generally as a default, a LED (the 95% lower conhdence limit on a dose associated with an extra tumor risk) chosen to be representative of the lower end of the observed range, to the origin (zero dose/zero response), corrected for background incidences. This implies a proportional (linear) relationship between risk and dose at low doses (note that the dose-response curve generally is not linear at higher doses). The slope of this line, known as the slope factor, is an upper-bound estimate of risk per increment of dose that can be used to estimate risk probabihties for different exposure levels. The slope factor is equal to O.OI/LEDqi if the LEDqi is used as the POD. 

There is a continuing debate as to whether inbred or outbred strains of rodents should be used. In theory, inbred strains are preferable because a more accurate knowledge of back-grormd tumour incidence is available. It may be, however, that a particular inbred strain may metabolise the test material in a certain way or have a genetic resistance to the development of a specific tumour type. Usually outbred strains of rat or hamster are used, but occasionally inbred mice strains are included. An FI hybrid mouse strain is frequently employed. In some circumstances outbred Syrian hamsters may be the species of choice. The most important factor is to have a sound knowledge of the background incidence of tumours in the species or strain selected. This information complements the concurrent control data and provides information on the susceptibility of the strain to rare tumour t)rpes. Modif)dng factors, such as diet, cage density, etc., must be kept as constant as possible to enable correct interpretation of the results. ... 

In Phase I and II studies, T)tpe A reactions are by far the most frequent. T)tpe B are rare, which is fortunate as some can be serious or even fatal. Table 7.1 shows the number of subjects that need to be studied to give a good chance (95%) of detecting an adverse event when there is no background incidence. The problem is many orders of magnitude worse if the adverse reaction closely resembles spontaneous disease that has a background incidence in the trial population. 

Previous experience with the medicine and background incidence of reaction in this disease group. 

Another contributory factor in imderreport-ing is the background incidence of the condition in the overall patient population. The chances of identifying a clinical condition that occurs in the population only extremely rarely as a drug-related event is clearly much greater than if it... 

The following data (Table 3.4) are taken from Piccart-Gebhart et al. (2005) who compared trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer with observation only. The binary outcome here is one or more serious adverse events (SAEs) versus no SAEs during the one year trial. The rate in the observation only group provides the background incidence of SAEs. 

It is difficult to justify, therefore, any use of trazodone in boys, adolescent males, or young men, especially given its relatively limited usefulness as an antidepressant or even a sedative. Even in girls its use is questionable. Nefazodone would appear to be a far better alternative, especially in that it has no recognized sexual side effects, is well tolerated once the patient adapts to the sedative effect, and is not associated with priapism. That is, risks do not include a known increase in priapism above the background incidence (Thompson et ah, 1990 Feiger et ah, 1996 Pecknold and Langer, 1996). 

Travis and Hester (1990) use the estimated lifetime exposures of the U.S. population to these "background" chemicals (as estimated by EPA exposure studies) combined with the estimated potency of the exposures (derived from the animal experiments of the NTP) to conclude that lifetime cancer risk from these chemical exposures is between 0.14 and 0.50 percent. If the risk from exposure to background chemicals is added to the risk from exposure to naturally occurring radioisotopes—the background incidence of cancer is between 1.0 and 1.5 percent in the U.S. population. ... 

When 22 men and 38 women who had taken lithium for at least a year (mean 6.9 years) for bipolar disorder were evaluated for adverse effects, hypothyroidism requiring thyroid supplementation was found in 16 (14 women and 2 men) 9 had a goiter (637). The area from which some of the patients came was known to have a high background incidence of thyroid dysfunction. 

Stochastic responses are those for which the probability, but not their severity, is a function of dose, without threshold. Because of the long latency period between exposure and the expression of a stochastic response, the existence of a causal relationship between dose and response can only be inferred on statistical grounds based, for example, on knowledge of the background incidence of the response of concern in unexposed populations. Severe hereditary (genetic) and many carcinogenic (e.g., genotoxic) responses are considered to be stochastic. 

Several conclusions were drawn from these rodent study results. First, the increased incidence or earlier onset of mammary tumors occurred only in SD rats, an animal with a normally high spontaneous background incidence of the tumors (44% grand mean in the studies illustrated in Table 26.1). Second, tumor histology showed qualitatively identical pathology in treated and untreated rats. Third, tumor incidence in either control or treated groups never reached... 

Sufficient numbers of control animals should be employed. The use of such controls allows a determination of normal values for features monitored in the study and background incidence of pathology in the population studied detection of the onset of adverse conditions, eg, infection, which are unrelated to, and detrimental to, the conduct of the study, and deviation of monitored features between controls and exposed animals, which may indicate a treatmentrelated effect. 

Factors to account for various uncertainties are applied to the NOAEL, LOAEL, or BMD to derive a UEL. The total size of the uncertainty factor (UF) varies, accounting for assumed or known interspecies differences, variability within humans, quality and quantity of the data, consistency, slope of the dose-response curve, background incidence of the effects, and pharmacokinetic data. The relevance of the species, type of effect, dose, route, timing, and duration of exposure are additional factors that might influence its size. A discussion of UFs is provided in several papers (e.g., Lewis et al. 1990 Renwick 1991,1998 Dourson et al. 1996 Renwick and Lazarus 1998). 

Many of the diseases that can be caused by chemicals can also be due to other causes. Cancer is not a single disease but many different diseases, and generally chemicals cause a particular t5rpe of cancer rather than a mixture of t5rpes. Even so there is usually a background incidence in the population as a whole, and demonstrating an increased incidence is sometimes statistically difficult. Similarly, other disorders, Hke malformations in babies or liver disease, can have many causes including infections. 

The TD50 is a conceptual, interpolated value similar to the UCR. The TD50 corresponds to the dose that would cause cancer in 50 percent of the treated animals beyond background incidence from control animals. Higher toxicity is indicated by a higher UCR and a lower TD50 value. When the same assumptions are used to calculate both, the UCR can be estimated as shown in equation 7.6. 

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