Textbook, 2013, 81 Pages
LIST OF TABLES
LIST OF FIGURES
LIST OF ABBREVIATIONS
Significance of Topic
Chapter 1 (Dose effects of vitamin E on lung cancer risk)
Chapter 2 (Empirical vitamin E-lung cancer risk models)
Chapter 3 (Mechanism-based vitamin E-lung cancer models)
Chapter 4 (Conclusions and implications)
Study One: The Vital Cohort
Study Two: The ATBC Cohort
CHAPTER 1: DOSE EFFECTS OF VITAMIN E ON LUNG CANCER RISK
Characteristics of Dose Effect of Vitamin E on Lung Cancer Risk
CHAPTER 2: EMPIRICAL VITAMIN E-LUNG CANCER RISK MODELS
Empirical Dose-Response Models
Dose-Response Models Linking Vitamin E Intake to Lung Cancer Risk
The VITAL Cohort
The ATBC Cohort
Interpretation of Doses
Uncertainties in Estimates
CHAPTER 3: MECHANISM-BASED VITAMIN E-LUNG CANCER MODELS
Mechanism-Based Dose-Response Models
Mechanism-Based Vitamin E-Lung Cancer Models
Vitamin E-Induced Tumor Cell Apoptosis
Fas Signaling Pathway
Transforming Growth Factor-β Pathways
Sphingolipid Pathway: Effects of γ-Tocopherol on Prostate Cancer Cells
Sphingomyelin Signal Transduction Pathway
CHAPTER 4: CONCLUSION AND IMPLICATIONS
Table 1. Hazard Ratios for Lung Cancer Associated with 10-year Use of Supplemental Vitamin E in the VITAL Study
Table 2. Hazard Ratios for Lung Cancer Associated with 10-year Use of Supplemental Multivitamins in the VITAL Study
Table 3. Hazard Ratios for Lung Cancer Associated with 10-year Use of Supplemental Multivitamins Stratified by Smoking Status in the VITAL Study
Table 4. Hazard Ratios for Lung Cancer Associated with 10-year Use of Supplemental Vitamin E Stratified by Smoking Status in the VITAL Study
Table 5. Multivariate Relative Risk of Lung Cancer According to Quintile of α-Tocopherol, Stratified by Trial Intervention Arm, in the ATBC Study
Table 6. The Safe versus Critical Doses of Supplemental Vitamin E Use versus Dietary Vitamin E Use in the VITAL and ATBC Studies
Figure 1. Schematic representation of the Fas-FADD signaling pathway
Figure 2. Schematic representation of the TGF-β signaling pathway or the SMAD signaling pathway
Figure 3. Schematic representation of DAXX, JNK, and p53 pathways
Figure 4. Schematic representation of sphingomyelin and Rac-1 pathways
illustration not visible in this excerpt
This introduction provides a brief overview of the global and scientific relevance of this topic, how vitamin E has been linked to lung cancer risk, followed by a brief outline of book highlights and key areas, including research questions, covered in this book. It also offers summaries of the two selected studies, one conducted by Slator et al. (2008) and one by Writh et al. (2004) that will be discussed and analyzed in details in the second chapter.
Lung cancer is a serious illness and a public health crisis that affects millions of people worldwide. It is one of the most common and dangerous forms of cancers, accounting for 1.3 million deaths annually (WHO, 2009). This type of cancer is particularly deadly because its cells are highly metastatic (i.e., spread) and can enter the blood and spread to form tumors in other parts of the lung, or in other organs, such as the liver and the brain (Solomon et al., 1996). Further, during the final part of the twentieth century, the global cancer burden increased by twofold, and it is expected that this increase will continue at the same level between 2000 and 2020, and will triple by 2030 (WHO, 2008). Worldwide cancer mortality has been estimated to be as high as 12 million deaths in 2030 (WHO, 2009).
To improve the health of future generations, and acknowledging that not all smokers develop lung cancer, medical researchers have intensified their efforts to clarify the role of diet in lung cancer development. In this context, many researchers have explored whether there is a relationship between vitamin E intake and lung cancer risk. Vitamin E, a fat-soluble antioxidant, includes several tocopherol and tocotrienol derivates (Comitato et al., 2009). In most cases, antioxidants are important part of our diet; they can inhibit the oxidation of other molecules and protect cells from damage caused by free radicals (Solomon et al., 1996). Vitamin E, in particular, can deactivate free radicals, inhibit proliferation and induce apoptosis in a large number of cancer cells (Comitato et al., 2009); hence, it has the capacity to prevent some of the oxidative damage that may possibly cause (lung) cancer. As a result, diets rich in antioxidants, such as vitamin E, have been recommended to reduce the risk of developing cancers (Key et al., 2002). And yet, the dose-response effects of vitamin E intake on lung cancer risk and the molecular mechanism(s) involved in its action are still unclear.
This topic is relevant globally. According to WHO, there is evidence that effective cancer control measures will reduce the incidence of cancer significantly (WHO, 2008). Already in 2003, WHO argued that smoking cessation, healthy diet, and infection control would prevent as many as one third of cancers worldwide (WHO, 2003). Additionally, cancer has moved from being the disease of the wealthy in developed countries to becoming the disease of the poor in developing countries, where health care has traditionally been regarded as low priority (WHO, 2008). Health systems around the globe are facing severe challenges in terms of providing treatment to individuals suffering from cancers, including those of the lungs. In certain areas, limited funding prevents many cancer patients from receiving program benefits. This lack of funds may also prevent medical researchers from developing new treatments, and novel prevention approaches. All these factors have serious implications on society as a whole. Nevertheless, despite the global and scientific relevance of the topic, human biological systems (in different parts of the world) are far from uniform, and it is not easy to determine whether the risk of developing lung cancer is reduced or increased by exposure to vitamin E during different phases of human life.
This book explores different aspects of the dose-response relationship of vitamin E and lung cancer risk, focusing on assessing the empirical dose-response models of dietary and supplemental vitamin E intake on lung cancer risk and identified and proposed mechanism-based models. Although such an assessment may seem complicated and difficult at first, the book proposes a coherent, structured and progressive framework that can be useful not only when evaluating vitamin E intake, but also that of other micronutrients, macronutrients, or even toxic chemicals in relation to not only lung cancer, but also other types of cancer or chronic diseases.
Individual chapters emphasize, wherever possible, existing knowledge on biological processes (within the cells) that are capable of selectively inducing apoptosis of potential tumor cells. Thoughtful discussion is also given to the types of data available from research studies that have the potential to impact the development of dose-response models. Throughout the book, knowledge gaps relating to the evaluation of vitamin E dose-response are identified. This book highlights that, while significant achievements have been made in recent years, gaps in knowledge are still wide, and they constitute considerable constraints to the development of effective, novel and appropriately targeted (lung) cancer strategies. It is believed that understanding these gaps and their implications can guide the design of new dose-response studies that will add to our knowledge of vitamin E activity and shed light on issues related to its dose-response.
In particular, the book attempts to draw attention to the following questions:
What does previous research reveal about whether dietary and supplemental intakes of vitamin E affect the risk of developing lung cancer?
What is the shape of the dose-response curve for lung cancer risk at various doses of vitamin E?
What is the safe or beneficial dose of vitamin E in relation to lung cancer risk?
What is the critical dose at which no beneficial effects of vitamin E are observed? What are the empirical dose-response models and the mechanisms-based models of vitamin E that have been investigated previously with respect to lung cancer?
Chapter 1 (Dose effects of vitamin E on lung cancer risk). The first chapter of the book generally emphasizes that the main advantage associated with conducting a dose-response analysis of vitamin E intake in relation to lung cancer risk is to detect and quantify the relationship between the dose of vitamin E and its effect on lung cancer development. This opening chapter outlines the broad principles of dose-response modeling and reviews very briefly some defining aspects of carcinogenesis in lung cancer, and the characteristics of dose effects of vitamin E on lung cancer risk.
Chapter 2 (Empirical vitamin E-lung cancer risk models). The second chapter builds on these characteristics by assessing the strengths and weaknesses of two research studies, namely "Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer" by Slatore et al. (2008) and "Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers" by Wright et al. (2004). The main objective was to report on estimates of safe and critical dietary and supplemental doses of vitamin E consumption. Beneficial dietary and supplemental doses of vitamin E among Finish men aged 50-69 years who smoked five or more cigarettes per day and American men and women aged 50-76 years, respectively, are compared to their corresponding critical doses. An in-depth reflection on the methodology and data analysis employed by the researchers necessitated a focus on the complexity of the models presented, the interpretations that were made, and the uncertainties associated with not only the dose estimates of dietary and supplemental consumption of vitamin E, but also those associated with extrapolation of dose- response curves.
Chapter 3 (Mechanism-based vitamin E-lung cancer models). The third chapter presents several possible mechanisms and biological processes driving the development of lung cancer and connecting it to vitamin E status in serum or tissue. It provides detailed discussion on Fas signaling and transforming growth factor-beta pathways in a comprehensive literature review. It then goes on to discuss and, to a certain degree, evaluate the different modeling approaches. This chapter finds that the sphingomyelin signal transduction pathway and Rac1 pathway may be novel mechanism-based vitamin E-lung cancer models that have not yet been evaluated properly.
Chapter 4 (Conclusions and implications). The overall conclusions and implications are stated clearly in the final part. As the chapters in this book demonstrate, challenges involved in examining dose-response relationships of vitamin E and lung cancer risk can be recognized as some of the major barriers to developing and implementing a cohesive approach to lung cancer prevention, early detection, and treatment.
Before presenting each chapter, it is imperative to provide brief summaries of the two cohort studies that will be evaluated extensively in the present assessment.
In the article "Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer," which appeared in the American Journal of Respiratory and Critical Care Medicine in 2008, Christopher G. Slatore, Alyson J. Littman, David H. Au, Jessie A. Satia, and Emily White examined the association of supplemental multivitamins, vitamin E, vitamin C, and folate with the incidence of lung cancer (Slatore et al., 2008). Acknowledging the fact that lung cancer is the leading cause of cancer-related mortality in the United States, they explored data from a prospective cohort of 77,721 men and women aged 50-76 years from Washington State in the VITAL (VITamins And Lifestyle) study. Lung cancer cases were identified through the Seattle-Puget Sound SEER (Surveillance, Epidemiology, and End Results) cancer registry, which is reliable for lung cancer histology. Using a commercial list, 364,418 VITAL-supplement-questionnaires were mailed from October 2000-December 2002, and a total of 77,719 (21.3%) individuals who returned the questionnaires were identified as eligible subjects. Baseline data were collected, and the Institutional Review Board of the Fred Hutchinson Cancer Research Center approved the protocol.
Participants were monitored until 31 December 2005 by linking them to the Seattle-Puget Sound SEER registry. Mortality was ascertained through linkage to Washington State death files, while moves out of the area were obtained by linking the cohort to the National Change of Address System and by follow-up letters and telephone calls. The covariates included in this study were tobacco, body mass index (BMI), socioeconomic and anthropomorphic factors, as well as previous history of cancer and self-report of physician-diagnosed chronic obstructive pulmonary disease (COPD) and/or asthma. All statistical analyses were performed using Stata SE-9 (StataCorp, College Station, TX), and Cox regression was employed to estimate the hazard ratios (HR s) for associations of supplemental multivitamin, vitamin E, vitamin C, and folate use with lung cancer. To be more precise, the measurement was HR s for incident lung cancer according to 10-year average daily or weekly use of supplemental multivitamins, vitamin E, vitamin C, and folate. Slatore and colleagues also examined the associations between different lung cancer morphologies and supplemental vitamins, as well as the differences of the supplement-lung cancer associations by subgroups defined by smoking status. A total of 521 cases of lung cancer were identified. Adjusting for smoking, age, and gender, there was no inverse association with any supplement, whereas supplemental vitamin E was associated with a small increased risk of lung cancer (HR, 1.05 for every 100-mg/d increase in dose; 95% CI = 1.00-1.09; p = .033) (Slatore et al., 2008). The risk was greatest for non-small cell lung cancer (HR, 1.07 for every 100-mg/d increase; 95% CI = 1.02-1.12; p = .004) and was largely confined to current smokers (HR, 1.11 for every 100-mg/d increase; 95% CI, 1.03-1.19; p = .01). The study concluded that patients should be advised not to take vitamin E supplements to prevent lung cancer.
The second article that is identified for critique and evaluation in this paper is entitled "Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers." Hypothesizing that multiple antioxidants simultaneously may be important in terms of risk estimation, Margaret E. Wright, Susan T. Mayne, Rachael Z. Stolzenberg-Solomon, Zhaohai Li, Pirjo Pietinen, Philip R. Taylor, Jarmo Virtamo, and Demetrius Albanes constructed a dietary antioxidant index and evaluated its ability to predict lung cancer risk within the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study cohort (Wright et al., 2004). The latter was a randomized, double-blinded, placebo-controlled primary chemoprevention trial with a 2 × 2 factorial design that tested whether supplementation with vitamin E (50 mg of dl-α-tocopherol/day) and β-carotene (20 mg/day) reduced the incidence of lung cancer (The ATBC Cancer Prevention Study Group, 1994).
At baseline (1985-1988), 27,111 Finnish males aged 50-69 years who smoked five or more cigarettes daily and were willing to provide written informed consent completed a dietary questionnaire that covered both food and beverages. Further, the institutional review boards of both the National Public Health Institute of Finland, and the US National Cancer Institute approved the study. Incident primary cancers of the lung or bronchus were ascertained via the Finnish Cancer Registry, while administration of a chest radiograph at baseline ensured that men with apparent lung cancer were excluded from the trial. In addition, three follow-up chest radiographs were performed during the trial and at study exit. A total of 1,787 incident cases of lung cancer were identified during a follow-up period of up to 14.4 years (1985-1999, median, 11.3 years). Histologic verification was available for 95% of all cases.
Principal components analyses were individually applied to the vitamin E (α-tocopherol, γ-tocopherol, α-tocotrienol, and β-tocotrienol), carotenoid (α-carotene, β-carotene, β- cryptoxanthin, γ-carotene, lutein + zeaxanthin, and lycopene), and flavonoid (catechin, epicatechin, kaempferol, myricetin, and quercetin) nutrient groups, and summation of retained principal component scores, plus selenium and vitamin C, yielded the composite antioxidant index. These antioxidant nutrients were frequently consumed in this cohort. The results indicated that, within each arm of the trial, risks of lung cancer were 13-18% lower among participants in the highest antioxidant index quintile compared with the lowest. Additionally, in multivariate proportional hazards models, the relative risks for lung cancer according to increasing quintiles of the antioxidant index were 1.00 (referent), 1.00 (95% CI: 0.87, 1.14), 0.91 (95% CI: 0.79, 1.05), 0.79 (95% CI: 0.68, 0.92), and 0.84 (95% CI: 0.72, 0.98) (p for trend = .002). Accordingly, Wright et al. (2004) concluded that their findings supported the hypothesis that a combination of dietary antioxidants reduced lung cancer risk in male smokers. Thus, a balanced diet rich in a variety of antioxidant nutrients was recommended because it may play an important role in the fight against lung cancer in smokers. The researchers stated, however, that the benefits appeared to be modest and that the fundamental strategy in the prevention of lung cancer should still be smoking cessation.
This chapter outlines the characteristics of dose-response relationships of lung cancer responses induced by various doses and sources of vitamin E. Whether or not knowledge of possible molecular mechanisms connecting vitamin E intake to lung cancer risk is helpful for the evaluation of dose-response models is also addressed. Admittedly, some of the targeted aspects may be difficult to address and therefore they have too often been overlooked in previous analyses, but are too important to be passed over. It is accepted by most investigators that most cellular responses to vitamin E require the initial interaction between vitamin E and the Fas Ligand and/or the inactive (latent) transforming growth factor-beta (TGF-β). Many of the biological responses to certain vitamin E compounds at the cellular level appear to depend on the induction of apoptosis in pulmonary epithelium and lymphoid cells. However, it must be kept in mind that the dose-response characteristics of vitamin E action are believed to be strengthened by additional mechanistic pathways that are yet to be identified.
Characteristics of Dose Effect of Vitamin E on Lung Cancer Risk
A dose-response relationship describes how the likelihood and severity of adverse health effects (i.e., the responses) are related to the different levels (i.e., the doses) of exposure to the factor of interest after a certain exposure time (U.S. EPA, n.d.). The shape of the dose-response relationship depends on the type of response (e.g., lung cancer risk, incidence of lung cancer, mortality) that is observed, the dose given that produced that response, and the subjects (e.g., humans, animals, or isolated lung cells or tissue) tested. For instance, the relationship observed for a response like "lung cancer risk" maybe different from the relationship observed for a response like "lung cancer mortality" or "lung cancer incidence." Besides, use of vitamin E supplements over an extended period of time (over 8 years) may increase the risk of developing lung cancer among American men and women aged 50-76 years (Slatore et al., 2008), whereas supplementing with small amounts of vitamin E may produce no observable effect in the same population or in other populations. To put it differently, different populations may respond differently at different doses and exposure times.
There are many advantages associated with conducting a dose-response analysis of the effects of vitamin E intake on lung cancer risk. The main advantage is that a dose-response analysis detects and quantifies the relationship between a dose of the exposure under consideration and its effect on human health, i.e., in the present context, an increasing intake of vitamin E and its effect on lung cancer development. Other advantages include making comparisons between the various forms of vitamin E across a wide dose range, and even with limited data, certain forms of vitamin E with similar mechanism of actions may have a similar shape or similar maximal effect (Mandema et al., 2005). Most importantly, the most compelling evidence of causality in epidemiological studies is the presence of a dose-response relationship
(NAS, 1995). That is, the demonstration of a trend in the lung cancer risk (or incidence) with degree or duration of vitamin E intake.
In relation to this analysis, two major elements can be distinguished: Dose and response. On the one hand, examples of dose include the amount of supplemental and dietary vitamin E taken by, for instance, cohort members at a given frequency. In other words, the magnitude of lung cancer risk that is caused by vitamin E exposure depends on the dose and frequency of vitamin E intake. The extent and magnitude of the effects of vitamin E are mediated through its ability to activate certain cell surface receptors (see Mechanism-Based Vitamin E-Lung Cancer Models in Chapter 3). This stimulation results in a sequence of biochemical events that are linked to particular biological functions, including cell cycle arrest and apoptosis, each of which may reflect simple (or light) responses with a low and time-limited exposure or complicated responses with high and prolonged exposure.
It is worthwhile here to emphasize that two of the biochemical effects of vitamin E that might have particular relevance to its protective effects are (a) its ability to inhibit cancer formation by quenching of free radicals; and (b) its control of tumor growth through the induction of differentiation and apoptosis (Kline et al., 2001). Additionally, although desired, the actual dose that cause a specific response (i.e., the activation of a specific mechanism of action) remains unknown, and the best estimates reported in this book are based on a number of assumptions and parameters presented in previous studies. The more well-designed the study is (i.e., the higher the precision and validity of the study), the closer the estimates are to the actual dose (i.e., the more confident the researcher would be in the obtained estimates). On the other hand, a response can be regarded as an observation or a result following exposure to vitamin E. Responses may include a wide spectrum of observations or outcomes, from simple biochemical reactions to complex events, some of which are tissue-specific and may be directly or indirectly, positively or inversely related to exposure dose. In this regard, research has demonstrated that cancer is caused by mutations in the DNA, and that carcinogens in tobacco smoke may trigger mutations in lung cells, leading in certain cases to lung cancer; thus, the causes of mutations in lung cells are believed to be the causes of lung cancer (MedlinePlus, 2013). However, one of the major challenges that face researchers is to figure out the biological pathways that start with genetic mutations and may result in a response like lung cancer. At the same time, research has revealed that vitamin E succinate (VES), i.e., the succinated form of RRR - α-tocopherol that is often used in vitamin E supplements, is a potent inducer of apoptosis in a wide range of human cancer cells and have been found to effectively induce apoptosis in a dose and time dependant manner (Kline et al., 2001). For instance, this derivative of vitamin E at a 50% effective concentration range of 5-10 mg/L is capable of inducing human lung (A549) cells to undergo apoptosis (Kline et al., 2001). An overall hypothesis for the mode of action of vitamin E, put forth by a number of researchers, is based on different pathways, many of which are related to the inhibition and/or activation of the expression of certain genes. This hypothesis has been most well characterized for the identification of SMAD3 as a repressor of human telomerase reverse transcriptase (hTERT) gene and the c-myc gene, i.e., the gene that contributes to the development of human cancers (Li et al., 2006). There is also some evidence indicating that the activation of p53 transcription factor is impaired in 55% of lung cancer patients who are smokers, compared to 38% of lung cancer patients who are former smokers (had stopped smoking 1-5 years earlier), and 25% of those who are nonsmokers (Husgafvel-Pursiainen & Kannio, 1996). The biological basis for these findings and their possible influence on suggested pathways is outlined in the following chapters.
Although gaps in knowledge still exist, research to date is consistent with the hypothesis that treatment with VES induces apoptosis in human cancer cells by converting latent inactive transforming growth factor-beta (TGF-β) to its active form and/or up-regulating the expression of Fas ligand, both of which represent the first steps in a series of biochemical and cellular changes that may define the benefits observed (Kline at al., 2001). The evidence that supports this theory has been presented in chapter 3 after conducting a comprehensive literature review (e.g., Pearson et al., 2001; Kline et al., 2001; Wajant, 2002; Takayama et al., 2001; Bignold, 2004; Sterner-Kock et al., Ishisaki et al., 1999; Wharton & Derynck, 2009; Hariharan & Pillai, 2008).
Finally, many of the known biological activities of tocopherols and tocotrienols also appear to follow their rank order of activating other apoptotic pathways, such as sphingomyelin signal transduction pathway and Rac1-induced apoptosis pathway (see chapter 3). The sphingomyelin pathway mediates apoptosis in several nonhematopoietic cells and holds for changes in concentration of several proteins, including the generation of ceramides, which leads to DNA fragmentation in sensitive cells (Haimovitz-Friedman, 1994). The direct relationship between vitamin E and the generation of ceramides is less clear. But although evidence are limited, it can be hypothesized that many of the biochemical effects produced by vitamin E in Fas signaling and TGF-β signaling pathways may also occur in sphingomyelin signal transduction pathway and Rac1-induced apoptosis. This hypothesis is novel because as of yet (a) only one study has revealed that a combination of vitamin E forms induces cell death in human prostate cancer cells by interrupting sphingolipid synthesis (Jiang et al., 2004); and to date (b) almost no studies have examined Rac1-induced apoptosis as a possible mechanism of action for vitamin E in relation to lung cancer risk.
Dose response modeling involves the development of computational (mathematical) systems and biological tools to predict and understand the dose-response relationship for certain components (e.g., combinations of vitamin E forms) at the cellular and tissue level of the target organ (i.e., human lung) (Zhang, n.d.). Such models are generally classified as either empirical models or mechanism-based models (Hoel, 1980). Both categories are briefly reviewed in the next chapters.
In this respect, human dose-response testing is based on epidemiological data that compares "exposed" to "unexposed" individuals. However, the "unexposed" study subjects may contain substantial amounts of background exposure to antioxidants, including vitamin E, in the absence or presence of other identified and unidentified risk factors. Also, the results of many epidemiological studies are hampered by small sample sizes, and in most cases, the actual amounts of vitamin E in human tissues are not examined. It is not often either that serum vitamin E levels are measured. In addition, in populations exposed to similar amounts of vitamin E (e.g., the population examined in Wright et al. study), some subjects may exhibit a reduced risk of lung cancer while others may not. This suggests that there may be multiple factors (e.g., genetic susceptibility, radon exposure) that may influence an individual's response to the dose of vitamin E consumed. Consequently, the concept of independent versus additive backgrounds must be taken into consideration (Hoel, 1980). Additive background implies linearity, while the assumption of total independence of background is necessary to justify nonlinearity at low doses (Hoel, 1980). This aspect has important implications to low-dose extrapolations for the purpose of risk estimation.
Dose-response models for ligand-receptor mediated pathways are supposed to use information on key associations between ligand-activated receptors and biological response. It should be noted here that at very low concentrations of vitamin E, the receptor occupancy of TGF-β and/or Fas receptor may occur, but it may not be enough to induce apoptosis. On the other hand, if there are a sufficient number of receptors per cell, the number of death-inducing signaling complexes formed can be significant even at low vitamin E levels. One advantage of this approach is that the mechanism of action of the exposure of interest (in this case vitamin E intake) is considered sensitive to changes in exposure concentration (i.e., the levels of vitamin E intake that reflect the levels of vitamin E in tissues) (Roth & Grunfield, 1985). Clearly, multiple dose-response models can be employed when dealing with ligand- receptor mediated pathways. More specifically, when there is a proportional relationship between receptor occupancy and biological response, occupancy of any number of receptors, such as type II and type I Serine-Threonine Kinases (STKs) (see chapter 3), would produce a response; however, the response is more likely to be detectable only if an adequate number of receptors are activated simultaneously. Thus, if the number of receptors occupied is very low, a simple model that describes the response as a linear function of dose will probably be appropriate. Nonetheless, such a simple model is inadequate to provide a complete picture of the complexity and diversity of the biological responses that are initiated by a single receptor that is receptive to vitamin E effects.
That said, the dose-response relationships for relatively simple responses (e.g., the translocation of DAXX from the nucleus to the cytoplasm; see chapter 3) are unlikely to be used to analyze and/or predict the dose-response relationships for complex responses, such as lung cancer development. As a result, it is imperative to take into account what is known and hypothesized about the biological responses before analyzing the mathematical models applied to the data at hand in the two reviewed studies.
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