4. Modelling Survival Data in Medical Research

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

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Hyaluronan as an Immune Regulator in Human Diseases

Pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone stimulate the gonads by regulating germ cell proliferation and differentiation. FSH receptors (FSH-Rs) are localized to testicular Sertoli cells and ovarian granulosa cells and are coupled to activation of the adenylyl cyclase and other signaling pathways. Activation of FSH-Rs is considered essential for folliculogenesis in the female and spermatogenesis in the male. We have generated mice lacking FSH-R by homologous recombination. FSH-R-deficient males are fertile but display small testes and partial spermatogenic failure. Thus, although FSH signaling is not essential for initiating spermatogenesis, it appears to be required for adequate viability and motility of the sperms. FSH-R-deficient females display thin uteri and small ovaries and are sterile because of a block in folliculogenesis before antral follicle formation. Although the expression of marker genes is only moderately altered in FSH-R −/− mice, drastic sex-specific changes are observed in the levels of various hormones. The anterior lobe of the pituitary gland in females is enlarged and reveals a larger number of FSH- and thyroid-stimulating hormone (TSH)-positive cells. The phenotype of FSH-R −/− mice is reminiscent of human hypergonadotropic ovarian dysgenesis and infertility.

https://www.pnas.org/content/pnas/95/23/13612.full.pdf

Impairing follicle-stimulating hormone (FSH) signaling in vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance

GUEST EDITORIAL PART I: ICRP STATEMENT ON TISSUE REACTIONS PART II: EARLY AND LATE EFFECTS OF RADIATION IN NORMAL TISSUES AND ORGANS - THRESHOLD DOSES FOR TISSUE REACTIONS IN A RADIATION PROTECTION CONTEXT ABSTRACT PREFACE EXECUTIVE SUMMARY GLOSSARY 1. INTRODUCTION 1.1. Purpose of report 1.2. Definition and nature of tissue reactions to ionising radiation 1.3. General principles of radiation effects in cells and tissues 1.4. References 2. RESPONSE OF TISSUES AND ORGANS TO RADIATION 2.1. Haematopoietic and immune systems 2.2. Digestive system 2.3. Reproductive system 2.4. Skin 2.5. Cardiovascular and cerebrovascular systems 2.6. Eye 2.7. Respiratory system 2.8. Urinary tract 2.9. Musculoskeletal system 2.10. Endocrine system 2.11. Nervous system 2.12. References 3. MODIFIERS OF NORMAL TISSUE RESPONSE 3.1. Terminology 3.2. Mechanisms of action 3.3. Influence of modifiers on radiation response in tissue 3.4. References 4. THRESHOLD DOSES IN RELATION TO RADIOSENSITIVITY OF ORGANS AND TISSUES 4.1. Introduction 4.2. Haematopoietic and immune systems 4.3. Digestive system 4.4. Reproductive system 4.5. Skin 4.6. Cardiovascular and cerebrovascular systems 4.7. Eye 4.8. Respiratory system 4.9. Urinary tract 4.10. Musculoskeletal system 4.11. Endocrine system 4.12. Nervous system 4.13. Conclusions 4.14. References ANNEX A. SUMMARY OF STUDIES OF EXPOSURE AND OPACITIES OR CATARACTS

ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs -- threshold doses for tissue reactions in a radiation protection context

Evaluation of testicular functions (production of sperm and androgens) is an important aspect of preclinical safety assessment and testicular toxicity is comparatively far more common than ovarian toxicity This chapter focuses (1) on the histological sequelae of disturbed reproductive endocrinology in rat, dog and nonhuman primates and (2) provides a review of our current understanding of the roles of gonadotropins and androgens The response of the rodent testis to endocrine disturbances is clearly different from that of dog and primates with different germ cell types and spermatogenic stages being affected initially and also that the end-stage spermatogenic involution is more pronounced in dog and primates compared to rodents Luteinizing hormone (LH)/testosterone and follicle-stimulating hormone (FSH) are the pivotal endocrine factors controlling testicular functions The relative importance of either hormone is somewhat different between rodents and primates Generally, however, both LH/testosterone and FSH are necessary for quantitatively normal spermatogenesis, at least in non-seasonal species

https://www.tandfonline.com/doi/pdf/10.1080/21565562.2014.996025

Endocrine control of spermatogenesis: Role of FSH and LH/ testosterone.

The measurement of serum FSH is useful in the diagnostic workup of the infertile male, but fails to predict the presence of sperm in testicular tissue. We investigated whether inhibin B reflects testicular morphology and the presence of sperm more accurately than FSH. Serum inhibin B and gonadotropin levels were determined in 91 infertile men undergoing diagnostic bilateral testicular biopsy. In 52 of the 91 patients multiple samples were taken for testicular sperm extraction (TESE). Inhibin B levels were (mean 6 SEM) 238 6 32 pg/mL in men with normal spermatogenesis (n 5 9), 102 6 18 pg/mL in men with spermatogenetic arrest (n 5 15), 98 6 16 pg/mL in hypospermatogenesis (n 5 23), 41 6 6 pg/mL in focal Sertoli cell-only syndrome (SCO; n 5 26), and 27 6 8 pg/mL in complete SCO (n 5 18). The percentage of SCO tubuli was more strongly correlated to serum inhibin B (r 52 0.58; P , 0.01) than to FSH (r 5 0.34; P , 0.05). Similarly, the percentage of tubules with elongated spermatids was significantly (P , 0.05) more strongly correlated to serum inhibin B (r 5 0.65; P , 0.01) than to FSH (r 52 0.4; P , 0.01). Thus, inhibin B is slightly more sensitive than FSH as an index of the spermatogenic status. Neither FSH nor inhibin B alone, however, could predict the type of spermatogenetic damage exactly. The combination of FSH and inhibin B had high diagnostic sensitivity (88%) and specificity (83%) for the presence of elongated spermatids in testicular biopsies. Sperm could be retrieved in 34 (65%) of the TESE patients. The combination of inhibin B and FSH measurement showed a sensitivity of 75% and a specificity of 73% when identifying patients in whom sperm could possibly be retrieved by TESE. We conclude that although the measurement of serum inhibin B improves the sensitivity of predictive tests for the presence of sperm in histology or for TESE, this parameter cannot accurately predict TESE outcome. (J Clin Endocrinol Metab 84: 2496 ‐2501, 1999)

Serum inhibin B in combination with serum follicle-stimulating hormone (FSH) is a more sensitive marker than serum FSH alone for impaired spermatogenesis in men, but cannot predict the presence of sperm in testicular tissue samples.

The testis fulfills two essential functions: production and maturation of the male gametes and synthesis and secretion of the sexual hormones.

https://www.springer.com/cda/content/document/cda_downloaddocument/9783540783541-c1.pdf

Physiology of Testicular Function

Developmental and reproductive toxicology testing in nonhuman primates (NHPs) has become more common due to the increasing number of biopharmaceuticals in drug development, since NHPs are frequently the only species to express pharmacologic responses similar to humans. NHPs may also be used to help resolve issues associated with small-molecule reproductive toxicology in traditional species (rodents and rabbits). Adequate designs in NHP are presented for developmental toxicity (embryo-fetal development, pre-postnatal development, enhanced pre-postnatal development), reproductive toxicity (male and female), and juvenile toxicity studies. Optional parameters that may be included in these studies are discussed, as are new study designs that consolidate multiple aspects of the reproductive assessment and thereby conserve the limited supply of sexually mature NHPs available for testing. The details described will assist scientists in pharmaceutical, regulatory, and contract research organizations who are involved in conducting these unique studies to optimize their design based on case-by-case considerations.

Developmental and reproductive toxicology studies in nonhuman primates.

Macaques provide excellent models for preclinical testing and safety assessment of female reproductive toxicants. Currently, cynomolgus monkeys are the predominant species for (reproductive) toxicity testing. Marmosets and rhesus monkeys are being used occasionally. The authors provide a brief review on physiology and endocrinology of the cynomolgus monkey ovarian cycle, practical guidance on assessment and monitoring of ovarian cyclicity, and new data on effects of social housing on ovarian cyclicity in toxicological studies. In macaques, cycle monitoring is achieved using daily vaginal smears for menstruation combined with cycle-timed frequent sampling for steroid and peptide hormone analysis. Owing to requirements of frequent and timed blood sampling, it is not recommended to incorporate these special evaluations into a general toxicity study design. Marmosets lack external signs of ovarian cyclicity, and cycle monitoring is done by regular determinations of progesterone. Cynomolgus and marmoset monkeys do not exhibit seasonal variations in ovarian activity, whereas such annual rhythm is pronounced in rhesus monkeys. Studies on pair- and group-housed cynomolgus monkeys revealed transient alterations in the duration and endocrinology of the ovarian cycle followed by return to normal cyclicity after approximately six months. This effect is avoided if the animals had contact with each other prior to mingling. These experiments also demonstrated that synchronization of ovarian cycles did not occur.

https://journals.sagepub.com/doi/pdf/10.1177/0192623308327412

Gerhard F. Weinbauer

Papers

Endocrine control of spermatogenesis: Role of FSH and LH/ testosterone.

Serum inhibin B in combination with serum follicle-stimulating hormone (FSH) is a more sensitive marker than serum FSH alone for impaired spermatogenesis in men, but cannot predict the presence of sperm in testicular tissue samples.

Physiology of Testicular Function

Developmental and reproductive toxicology studies in nonhuman primates.

Physiology and Endocrinology of the Ovarian Cycle in Macaques