Functional endpoints

The majority of early publications that can be reasonably identified as comprising immunotoxicology reported altered resistance to infection in animals exposed to various environmental or industrial chemicals. Authors logically concluded that xenobiotic exposure suppressed immune function since the immune system is ultimately responsible for this resistance to infection. Subsequent studies demonstrated that suppression of various cellular and functional endpoints accompanied or preceded increased sensitivity to infection, and that administration of known immunosuppressants likewise decreased host resistance. The human health implications of these studies, that chemical exposure reduced resistance to infection, drove the initial focus of many immunotoxicologists on functional suppression, and provided the theoretical and practical underpinnings of immunotoxicity testing. 

The physiological consequences of the gene product should be explored in these studies, particularly with totally novel gene products. In addition, all the standard toxicological evaluations should be carried out, including examination of functional endpoints in vivo including cardiovascular and respiratory effects, and so on. 

The usefulness of a given cell line will depend on which differentiated or neoplastic endpoints the cells express and/or whether the cell line is long-lived or immortal. Assessment of whether a cell line expresses specific metabolic or functional endpoints generally requires empirical analysis. The development of transformed/immortalized epithelial cell systems has been particularly significant, since these cells are responsible for 85-90% of all cancers and they often manifest a broad range of specialized functions in addition to their neoplastic phenotype [13, 16, 22-34],... 

Table 13.10 illustrates examples of functional endpoints that have been successfully incorporated into toxicology studies. The examples cover primarily, but are not limited to, the vital organ systems (i.e., cardiovascular, respiratory, and central nervous systems). The repeat-dose toxicology studies offer an ideal opportunity to compare the pharmacological... 

Physiological Function Endpoint M eth od/Tech n ique References... 

When adopting the functional redundancy principle, the emphasis is on ecosystem processes impacts are considered acceptable when functional attributes are not changed, despite possible effects on community structure. Functional endpoints are rarely more sensitive than structural ones (Ellis 1989 Kersting 1994 Klepper et al. 1999) however, an exception is found in the photosynthesis inhibitors such as the triazines and urea classes of herbicides. Effects on functional endpoints indicate the limit of functional redundancy within the stressed community. Once ecosystem processes have changed due to contamination, this is usually an indication of severe effects on structural endpoints. 

Because functional endpoints are normally not incorporated in the SSD, community structure is the target of concern. 

Is there specific concern for structural or functional endpoints ... 

Kersting K. 1994. Functional endpoints in field testing. In Matthiessen P, editor. Freshwater field tests for hazard assessment of chemicals. Boca Raton (FL) CRC Press, p 57-81. 

Fig. 1. Tracings of lung airflow and lung volume changes during spontaneous breathing in a conscious rat. Airflow was measured directly using a head-out plethysmograph chamber. The functional endpoints can be automatically calculated for each breath using a data acquisition and analysis software system.

This preceding discussion was not intended to convince one that the study of receptor binding is of limited utility, but rather that it should be accompanied by an examination of functional endpoints, with a realization of the potential challenges (and rewards) involved in relating the two. 

Kula, C. and Rombke, J. (1998) Evaluation of soil ecotoxicity tests with functional endpoints for the risk assessment of plant protection products - state of the art. Environmental Science and Pollution Research, 5, 55-60. 

Concentrations of compound to be used in omic investigations would ideally cause no measurable change in cell viability, i.e., LC0 or NOAEL, and induce cellular stress, as indicated by an appropriate stress marker such as supernatant lactate [55] or a functional endpoint such as trans-epithelial electrical resistance (TEER) for epithelial cells [56]. This concentration can be defined as the point of departure of decreased viability in the dose range finding experiments, i.e., the highest possible LC0. 

Herzyk DJ, Bugelski PJ, Hart TK, Wier PJ. Practical aspects of including functional endpoints in developmental toxicity studies. Case study immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero. Hum Exp Toxicol 2002 21 507-512. 

G. Stephenson, J. Week, Effects of Plant Protection Products on Functional Endpoints in Soil (EPEES), SETAC, Lisbon, 24—26 April 2002. 

Simplistically, approval to market a drug could be based on one positive, adequate, and well-controlled phase III study supported by a phase II study where the endpoint was a surrogate endpoint marker. For example, if it is accepted that chest x-ray findings may be indicative of pulmonary function deterioration and the claim for the drug will be preservation of pulmonary function, one adequate and well-controlled phase III study with a pulmonary function endpoint supported by one phase II chest x-ray positive finding adequately fulfills the requirements of the act. 

The integrated data evaluation argument (2) must also be carefully considered. It is, in a sense, the other side of the argument, which says that separate studies can best address the full range of functional endpoints of concern (as laid ouf in Table 1.7). Is one side a necessary and essenfial trade-off for the other ... 

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