Body surface area approach

The reasons for using these three measures and the advantages and disadvantages of their use have been described by Davidson et al. (1986) and Vocci and Farber (1988). In these papers, it is also explained why the body weight can be used in aU three cases. However, the body weight should be taken to the power of 1, 0.67, and 0.75 for the body weight approach, the body surface area approach, and the caloric requirement approach, respectively. These figures indicate that the approach used to correct for differences in body size will clearly affect the value of the NOAEL adjusted to the body size of humans. 

Adjustment for Differences in Body Size Body Surface Area Approach... 

The above-mentioned references thus indicate that the body surface area approach apparently is a more feasible approach than the body weight approach in terms of dose correction for differences in body size between experimental animals and humans. 

Vermeire et al. (1999) have noted that scaling on the basis of surface area or caloric demand can be considered more appropriate compared to extrapolation based on body weight however, they also noted that experimental work did not answer the question regarding which of these two methods is the most correct. Based on theoretical grounds, and supported by their own analyses, Vermeire et al. (1999) concluded that scaling on the basis of caloric demand to adjust oral NOAELs for metabolic size can be considered more appropriate compared with extrapolation based on body weight. It was also noted that an allometric exponent of 0.67, i.e., the body surface area approach, seems to better describe intraspecies relations. 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that humans, in most cases, seem to be more sensitive to the toxic effects of chemicals than experimental animals, and that the traditional 10-fold factor for interspecies differences apparently is too small in order to cover the real variation. It was also noted that a general interspecies factor to cover all types of chemicals and all types of experimental animals cannot be expected. It was concluded that a 10-fold factor for interspecies variability probably protects a majority, but not all of the population, provided that the dose correction for differences in body size between experimental animals and humans is performed by the body surface area approach (Section 5.3.2.2). If the dose correction is based on the body weight approach (Section 5.3.2.1), the 10-fold factor was considered to be too small in most cases. 

The other way to express a relative dose in animals or humans is to do so in terms of body surface area. There are many reasons for believing that the surface area approach is more accurate for relating doses between species (Schmidt-Nielson, 1984), and especially between test animals and humans, but this is still a less common approach in safety assessment, although it is the currently accepted norm in several areas carcinogenesis and chemotherapy, for example. 

The surface area approach has been proposed as an alternative to correction for differences in body size based on body weight. This approach is founded on the notion that the basal metabolic rate of vertebrates is a fundamental biological parameter, i.e., a final common expression of physiological and biochemical functions, which is remarkably well related to the body surface area across species and within species (Davidson et al. 1986). 

The most comprehensive attempt to assess interspecies differences in susceptibility to toxic responses, based on two different dose correction approaches (body weight versus body surface area), was pubhshed in the classic paper by Freireich et al. (1966, as reviewed in Davidson et al. 1986, Calabrese et al. 1992, Grbnlund 1992). The authors attempted to standardize various toxicological studies for 18 anticancer dmgs performed in adult mice, rats, hamsters, dogs, monkeys, and humans. The findings of this study led to the conclusion that the toxic effects of an agent were similar across species when the dose was measured on the basis of the body surface area. 

The National Research Council (NRC) published a report, Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for assessing of cancer risks. These general guidelines can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene indicates that two default options may no longer be tenable Humans are as sensitive as the most sensitive animal species and the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. 

Another recommendation was to examine the correlation matrix of the covariates prior to the analysis and determine whether any two covariates were correlated. If any two correlated covariates were found to be important predictor variables, one could possibly transform the variables into a composite variable, such as the transformation of height and weight into body surface area or body mass index, or to use only the covariate with the greatest predictive value in the model and not to include the other covariate. An untested approach would be to use principal component analysis and then use one or more of the principal components as the covariate in a model. 

CRYPTORCHIDISM Cryptorchidism, the failure of one or both testes to descend into the scrotum, affects up to 3% of fuU-term male infants, becoming less prevalent with advancing postnatal age. Cryptorchid testes have defective spermatogenesis and are at increased risk for developing germ cell tumors. Hence, the current approach is to reposition the testes as early as possible, typically at 1 year of age but definitely before 2 years of age. The local actions of androgens stimulate descent of the testes thus, hCG can be used to induce testicular descent if the cryptorchidism is not secondary to anatomical blockage. Therapy usually consists of injections of hCG (3000 lU/m body surface area) intramuscularly every other day for 6 doses. 

An alternative method is the prospective approach, which uses patient information, such as serum creatinine, patient s age, weight, height, or body surface area to empirically estimate V, K, and creatinine clearance (Cl ). Adjustments to a maintenance dose are achieved through various approaches. The most significant application of either the retrospective or prospective approach is with regard to dosing adjustment in renal failure. ... 

The similarities in VX sensitivity between sheep and humans may, in part, be accounted for by similarities in rates of metabolic detoxification of the agent. The latter can be estimated from a comparison of body surface areas (based on body weight) as is done for animal-to-human extrapolations used in EPA cancer risk assessments (USEPA 1996c). Using this approach, the human equivalent dose for the 0.06 ig/kg/d sheep LOAEL in the Rice et al. study can be calculated as ... 

The Cockcroft and Gault (CG) equation [6] has been shown to overestimate GFR with the use of standardized creatinine assays. The CG equation is reported in units not adjusted for body surface area (BSA), which is appropriate for drug dosage adjustment. However, it is worth noting that the CG equation considers the body weight in the mathematical approach. 

Relatively few drugs marketed in the United States (approximately 20%) have pediatric dosing information available. Clinical trials had rarely been done specifically on pediatric patients. Traditionally, dosing regimens for children have been derived empirically by extrapolating on the basis of body weight or surface area. This approach assumes that the pediatric patient is a young adult, which simply may... 

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