Guidance for Industry 

Nonclinical Evaluation of 

Late Radiation Toxicity of 

Therapeutic 

Radiopharmaceuticals  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
November 2011 

Pharmacology and Toxicology 

   
Guidance for Industry 

Nonclinical Evaluation of 

Late Radiation Toxicity of 

Therapeutic 

Radiopharmaceuticals  

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 
 
Silver Spring, MD   20993-0002 
 
Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
 
November 2011 

Pharmacology and Toxicology 

 
   
TABLE OF CONTENTS 

 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   ACUTE VS. LATE RADIATION TOXICITY.............................................................. 3 
 
IV.   NONCLINICAL LATE RADIATION TOXICITY STUDIES .................................... 4 
 
A.   Study Goals.....................................................................................................................................4
  
B.   Study Design...................................................................................................................................5
  
1.  Good Laboratory Practices .............................................................................................................5
  
2.  Species Selection..............................................................................................................................5
  
3.  Timing of Study................................................................................................................................6
  
4.  General Study Design......................................................................................................................6
  
5.  Dose Levels ......................................................................................................................................7
  
6.  Clinical Pathology ...........................................................................................................................7 
 
7.  Necropsy and Histopathology..........................................................................................................7 
 
V.   CONCLUSIONS ............................................................................................................... 7
  
REFERENCES.............................................................................................................................. 9 
 
GLOSSARY................................................................................................................................. 11 
 
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic 

Radiopharmaceuticals 
 
 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
The objective of this guidance is to provide recommendations to industry for designing 
nonclinical late radiation toxicity studies to determine potential late radiation effects of 
therapeutic radiopharmaceutical agents.  The purpose of conducting nonclinical late radiation 
toxicity studies is to help minimize the risk of late-occurring radiation toxicities in clinical trials 
of therapeutic radiopharmaceuticals.  Because there are other guidances available for 
conventional nonclinical safety studies,2 this guidance focuses solely on late radiation safety 
concerns that are unique to therapeutic radiopharmaceuticals.  These unique safety concerns 
result from the risk of irreversible late radiation toxicity when these agents deliver high doses of 
ionizing radiation to normal organs.   
 
This guidance is not intended to address late radiation toxicity of radiobiologicals (e.g., 
radiolabeled monoclonal antibodies).  Biotechnology-derived products are excluded for the same  
reasons articulated in the ICH guidances for industry M3(R2) Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and S6 
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.3  This guidance is also 
not intended to apply to diagnostic radiopharmaceuticals whose low doses are not expected to 
elicit late radiation toxic effects. 
 
                                                 
1 This  guidance has been  prepared by the Late Radiation  Toxicity Working  Group, which includes representatives 
from the Center for Drug Evaluation and Research (CDER)  at the Food and Drug Administration. 
 
2  See the  FDA Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
1 
 Contains Nonbinding Recommendations 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
 
II.  BACKGROUND 
 
Therapeutic radiopharmaceuticals are typically administered systemically to treat cancer.  For 
cancer therapy with curative intent, the radiation absorbed doses delivered by therapeutic 
radiopharmaceuticals are comparable to those delivered with external beam radiotherapy (XRT) 
and are orders of magnitude higher than doses delivered by diagnostic radiopharmaceuticals.  At 
therapeutic doses of radiation, the late radiation toxicities commonly associated with XRT (e.g., 
renal, pulmonary, neurologic, late bone marrow failures) can also be seen with therapeutic 
radiopharmaceuticals.  With XRT, if the total dose given to an organ is less than its tolerance 
dose, the probability of symptomatic late radiation toxicity to that organ will be minimal (Perez 
et al. 2004). This type of toxicity should not be confused with the radiation-induced secondary 
malignancies for which the risk is known and accepted as unavoidable.  The tolerance doses of 
most human organs for conventionally fractionated XRT are known and are routinely used to 
direct the administration of XRT at a dose and schedule that minimizes late toxicity.  In the 
FDAs experience, however, there are few clinical data from which to estimate organ tolerance 
doses for therapeutic radiopharmaceuticals.  
 
Organ tolerance doses for systemically administered therapeutic radiopharmaceuticals can differ 
significantly from the published tolerance doses for conventionally fractionated high dose rate 
XRT.  With XRT, the dose received by an organ is determined by its proximity to the primary 
radiation beam and the tumor.  Organs within the primary radiation beam and in close proximity 
to the tumor are at greatest risk.  In the case of systemically administered radiopharmaceuticals, 
the dose received by each organ is determined primarily by the pharmacokinetics and 
biodistribution of the radiopharmaceutical agent.  In addition, the range and type of the radiations  
emanating from the source organ are critical.   
 
Radiolabeled drug-based therapy is an emerging and complex field with many potential dose 
modifying factors such as dose rate and fractionation.  Experience with external beam therapy 
demonstrates that with therapeutic doses of radiation a relatively small percentage change in total 
dose could lead to a large change in the probability of complications after the tolerance limit of  
an organ has been reached. The organ tolerance doses for XRT are based on conventionally 
fractionated high dose rate therapy.  Fractionation allows for repair of radiation damage between 
fractions. In contrast, therapeutic radiopharmaceuticals usually deliver a single dose of radiation 
at a low dose rate, where damage and repair of that damage occur simultaneously as competing 
processes. Therefore, organ tolerance doses for systemically administered therapeutic 
radiopharmaceuticals are not directly comparable to those for XRT.  In fact, late radiation 
toxicity has been observed with therapeutic radiopharmaceuticals at estimated organ doses that 
were below the XRT tolerance doses for the target organs (Giralt et al. 2003).  The entity of low 
  2
  Contains Nonbinding Recommendations 
dose hypersensitivity may account for the discrepancy as could anatomic concentration of 
isotope not captured in the dosimetry software (Joiner et al. 2001; Marples et al. 2004). 
 
Irreversible late radiation toxicities in the kidneys and bladder were observed in clinical trials 
with two therapeutic radiopharmaceutical agents where administered doses were estimated based 
upon external beam tolerance dose limits.  In one trial of radiopharmaceutical treatment of 
multiple myeloma, 30 out of 83 patients developed renal dysfunction.  Seven patients developed 
severe thrombotic microangiopathy (TMA) that required renal dialysis, and five of the seven 
patients died (Giralt et al. 2003). In a second clinical trial of 36 patients receiving 
radiopharmaceutical therapy for somatostatin receptor-positive tumors, five patients developed 
TMA; three of whom progressed to end stage renal failure (Moll et al. 2001).  These toxicities 
were not immediately recognized as complications of the treatment because they did not begin to 
occur until at least 3 months after radiopharmaceutical therapy.  This type of delayed onset is 
typical of late radiation toxicity. 
 
Therefore, there is a need to gain additional knowledge in this area to support the safe 
administration of therapeutic radiopharmaceuticals to humans.  Because studies in humans would 
be unethical, the best means to gain insight into this issue is by conducting nonclinical late 
radiation toxicity studies.  These studies will aid in identifying organs at risk and establish a 
margin of safety for late radiation toxicity.  As a result, these studies will help to minimize the 
risk of late-occurring radiation toxicities in clinical trials of therapeutic radiopharmaceuticals. 
 
 
III.   ACUTE VS. LATE RADIATION TOXICITY   
 
Ionizing radiation causes injury to cells and tissues mainly by damaging nuclear DNA (Hall 
2000), although non-DNA targets have been described (Coppes et al. 2005).  Most damaged cells 
continue to function normally until they die while attempting to undergo mitosis.  Thus the time  
frame in which radiation injury becomes clinically apparent is determined in part by cell turnover 
time.   
 
In organs with a rapid cell turnover (early reacting normal tissue) (e.g., bone marrow, epidermis, 
small intestine, and oropharyngeal mucosa), symptoms of radiation injury (e.g., bone marrow 
failure, desquamation, nausea, vomiting and diarrhea, and oral mucositis) appear within days to 
weeks of an acute dose of radiation.  Radiation injury to these organs is called early or acute 
radiation toxicity and is often self-limiting and reversible.  However, in organs with a slow cell 
turnover rate (late responding normal tissue) (e.g., the brain, spinal cord, heart, lungs, liver, 
kidneys, bone, and bladder), symptoms of radiation injury (e.g., brain necrosis, paralysis, 
pericardial and myocardial fibrosis with left ventricular failure, interstitial pneumonitis and 
pulmonary fibrosis, liver or kidney failure, osteoradionecrosis, and hemorrhagic cystitis) do not 
occur until after a latency period of several months to years during which relatively normal organ 
function continues. Radiation injury to these organs is referred to as late radiation toxicity and is 
usually progressive and irreversible (Yaes 1992; Tubiana et al. 1990; Fajardo et al. 2001). 
 
  3
  Contains Nonbinding Recommendations 
Because acute radiation toxicity becomes apparent within a short time period after 
administration, proximity in time to radiation exposure can be used as an important criterion in 
determining whether the radiopharmaceutical is the cause of a particular complication or adverse 
effect.  Such toxicities will become apparent early in a clinical trial and the trial can be revised or  
terminated, as appropriate.  In contrast, late radiation toxicity in organs such as the kidneys, liver, 
or central nervous system will not become apparent until months or years after treatment, 
necessitating longer term follow-up of treated patients.   
 
With XRT, radiation injury is often limited to organs within the radiation beams, because more 
distant organs receive much lower doses.  With radiopharmaceutical therapy, the risk of radiation  
injury to an organ is determined by both its intrinsic radiosensitivity and the concentration time-
activity curve of the agent in that organ.  For example, late radiation effects can occur if the 
kidneys receive a significant radiation absorbed dose from radiopharmaceuticals that are 
removed from the systemic circulation by glomerular filtration.  The kidneys are known to have 
a relatively low radiation tolerance dose (23 Gray (Gy)  for conventionally fractionated XRT); 
therefore, late radiation nephritis may be a dose-limiting toxicity for many therapeutic 
radiopharmaceuticals.  Although the bladder tolerance dose is considerably higher (65 Gy),  
hemorrhagic cystitis can occur as a late effect unless the bladder is adequately irrigated to 
reduce residency time. 
 
We believe that currently accepted methods, including software, for estimating radiation dose to 
specific tissue or organs may be acceptable for diagnostic amounts of radiopharmaceuticals.  
However, because the need for dose accuracy is higher for the determination of radiation doses 
for radiotherapeutic purposes, we consider these methods when used alone to be insufficient. 
 
 
IV.  NONCLINICAL LATE RADIATION TOXICITY STUDIES 
 
A.  Study Goals 
 
For treatment with therapeutic radiopharmaceuticals with curative intent, radiation absorbed 
doses comparable to doses delivered by XRT must be delivered to the tumor.  Because similarly 
high doses may be unavoidably delivered to normal tissue, radiation toxicities commonly 
associated with XRT may also be seen with radiopharmaceutical therapy.  Because the 
prescribed radioactivity is given with a small mass dose of the carrier, radiation toxicity, rather 
than pharmacological toxicity associated with the cold (nonradioactive) drug substance 
(formulation), is often dose-limiting.  In the past, nonclinical toxicity studies have been 
conducted mainly with the cold formulation.  Although these studies usually have shown that the 
no observable adverse effect levels (NOAELs) are many times the clinical mass dose, such 
studies assess the toxicity of the cold formulation only.  Therefore, to assess the potential risk of 
late radiation toxicity in humans, it is important to conduct late radiation toxicity studies in 
animals.  Such studies may allow the sponsor to: 
 
   Perform controlled experiments that are not ethically feasible in humans 
 
   Identify organs at risk for late radiation toxicity 
  4
  Contains Nonbinding Recommendations 
 
	   Establish a NOAEL for late-occurring, irreversible radiation effects in an appropriate 
animal species, to help select the clinical doses 
 
 	  Compare the biological effects and tolerance doses of radiation delivered with 
radiopharmaceutical therapy to those of radiation delivered by XRT in specific organs 
 
 	  Examine the pathologic changes and possible mechanism of injury 
 
 	  Distinguish the toxicity of radiopharmaceutical therapy from that of other concomitant 
therapies  
 
 	  Determine the amount of organ sparing that could be obtained by fractionating the 

radiopharmaceutical dose 

 
B.  Study Design 
 
There are challenges associated with the design and conduct of nonclinical late radiation toxicity 
studies. Therapeutic doses of radiopharmaceuticals require the administration of large amounts 
of radioactivity.  The animals and animal waste will be radioactive, requiring radiation 
precautions to protect personnel and the general public.  Precautions will also be necessary for 
the disposal of radioactive waste.  Despite these challenges, such studies have been conducted, 
and are recommended to optimize dosing and thus ensure safe clinical trials and patient care.  
Before initiating late radiation toxicity studies, the sponsor should discuss the specifics of the 
study design with the applicable review division and consider the following factors. 
 
1.  Good Laboratory Practices 
 
Late radiation toxicity studies conducted for the safety evaluation of a radiopharmaceutical drug 
product should be conducted in accordance with pre-existing requirements under the regulations 
for good laboratory practices (21 CFR part 58) and the Animal Welfare Act (7 U.S.C. 2131 et 
seq.). 
 
2.  Species Selection 
 
The sponsor should take into consideration the similarity in dosimetry, biodistribution, and 
pharmacokinetic profile of the radiopharmaceutical in the selected species and in humans.  
Suitable animal models to study late radiation toxicity are available.  In published studies, rats 
(Moulder et al. 1998; Moulder and Fish 1989; Molteni et al. 2000) and dogs (Prescott et al. 1990; 
McChesney et al. 1989) have been shown to develop late radiation nephropathy and pulmonary 
fibrosis after external beam irradiation.  Radiation-induced myocardial fibrosis has been shown 
to occur in rabbits (Fajardo and Stewart 1973) and dogs (Gavin and Gillette 1982).  The sponsors 
should discuss with the applicable review division alternative developmental programs when 
appropriate animal models are not available to study late radiation toxicity. 
 
  5
  Contains Nonbinding Recommendations 
3.  Timing of Study 
 
We recommend that the animal studies be scheduled to facilitate the conduct of clinical trials, 
including the selection of appropriate safety monitoring methods based on findings in such 
studies. To select the most appropriate species, human dosimetry and pharmacokinetic data 
using tracer doses should be obtained before initiation of the late radiation toxicity study.  
Several factors should be considered when assessing the relevance and the timing of the 
nonclinical studies: (1) the availability of human data following sufficient long-term follow-up 
in treated patients might obviate the need for such studies; and (2) the recognition that 
therapeutic radiopharmaceuticals are sometimes developed to treat patients with no other viable 
treatment options or for patients who will not survive long enough to be affected by late radiation 
toxicity. Ideally, the studies should be completed before the start of phase 2 dose escalation 
clinical trials, because late radiation toxicity may not be seen in the first dose cohort until after 
the entire trial has been completed.  However, a phase 2 trial can, based on risk-benefit 
considerations, be initiated before completion of the late radiation toxicity study. 
 
4.  General Study Design 
 
The study design should capture acute (occurring within the first few weeks after irradiation) as 
well as delayed (occurring after a prolonged latency) radiation effects.  Clinically, late radiation 
toxicity is not observed until at least several months to years following the radiotherapy.  In 
animals, late radiation toxicity usually occurs on a shorter timescale than in humans.  For 
example, the latent period for radiation nephritis in rats ranges from 3 to 7 months.  In dogs, 
renal dysfunction is observed by 10 months. Therefore, to obtain a reasonable estimate of the 
incidence of specific adverse effects, animals should be monitored for late radiation toxicity for 
at least 1 year after dosing. 
 
To the extent feasible, the nonclinical study design should closely mimic the design of the 
anticipated clinical trials including similar amount of injected radioactivity, number of doses, 
frequency of dosing, and dosing interval, as well as the relative tissue turnover rate and the 
relative biodistribution and pharmacokinetics in the animal species and human.  If both single 
and fractionated dosing will be studied in clinical trials, a two-arm study design evaluating late 
radiation toxicity after single as well as fractionated dosing may be necessary.  If planned 
radiation doses in humans will require hematopoietic growth factor support or bone marrow 
rescue, it may be necessary to support or rescue the irradiated animals so that they will survive 
comparable doses to allow for late radiation toxicity observations.  
 
Parameters that should be monitored are similar to those evaluated in expanded single- or repeat-
dose toxicity studies. These parameters include clinical observations, food consumption, body 
weight, ophthalmologic examination, hematology, clinical chemistry, urinalysis, and postmortem  
investigations (e.g., necropsy, organ weights, macroscopic and microscopic examinations).  
 
  6
  Contains Nonbinding Recommendations 
5.  Dose Levels  
 
Late radiation toxicity studies in animals should include at least four dose levels to identify the 
NOAEL and dose-related mild-to-severe late radiation toxicity.  The study should also include 
the cold formulation (ideally, the cold isotope equivalent to the highest mass dose) as a control 
group to distinguish specific radiation effects from potential pharmacological effects of the cold 
formulation.  The dose-limiting toxicities will be severe but are usually reversible (e.g., acute 
radiation toxicity related to the gastrointestinal tract, bone marrow).  Therefore, the highest dose 
selected should produce acute radiation toxicity.  This dose should be at least twice the 
maximum planned human dose or radiation tolerance dose for the critical organ (TD5/5 external 
beam radiation) identified as a possible dose-limiting factor in clinical trials.  The dose-multiples 
should be expressed in terms of body surface area and radiation absorbed dose to the critical 
organs, when critical organs have been identified.  The number of animals in each group should 
be sufficient to ensure survival of an adequate number to perform proper analysis at the 
completion of study.  
 
6.  Clinical Pathology 
 
Hematology, urinalysis, and clinical chemistries should be performed before dosing, 2 weeks 
after dosing, then once every 3 months afterward  and at termination.  In addition to a standard 
battery of hematology and clinical chemistry parameters, the study should also include the 
assessment of relevant biomarkers, if available, to identify late radiation toxicity for the target 
organ. For example, urinary glutathione-S-transferase isoenzyme levels can be monitored in 
addition to blood urea nitrogen and creatinine levels as markers for renal injury.  We recommend 
that the study design be developed in consultation with the FDA to ensure that appropriate long-
term toxicity indices are monitored.   
 
7.  Necropsy and Histopathology 
 
Necropsy, including organ weights and macroscopic examination of various organs, should be 
performed for all animals in the study, including those that died during the study observation 
period. Detailed histopathologic and microscopic evaluation should be performed at termination.  
 
 
V.  CONCLUSIONS 
 
Late radiation toxicity has been observed when the radiation absorbed doses from  
radiopharmaceuticals were based on external beam organ tolerance dose limits.  This is because 
the determinants for estimating the tolerance doses for the two radiation therapies are different.  
Therefore, there is a clear need to gain additional knowledge in this area to support the safe 
administration of these drug products.  Because studies in humans would be unethical, the best 
means to gain insight into the potential irreversible late radiation toxicity with these drug 
products is by conducting nonclinical toxicity studies.  These studies will aid in identifying at-
risk organs, establish a margin of safety for late radiation toxicity, quantify potential organ 
sparing when dose fractionation is used, and compare organ tolerance doses for 
  7
  Contains Nonbinding Recommendations 
radiopharmaceutical therapy to the published tolerance doses for conventionally fractionated 
high dose rate radiotherapy. 
 
Ideally, radiation toxicity studies in animals should be completed and analyzed before phase 2 
dose escalation toxicity trials are initiated in patients.  Until we have a better understanding of 
tolerance doses for radiopharmaceutical therapy, the safest way to proceed is to prescribe 
individualized doses to patients. 
 
 
  8
  Contains Nonbinding Recommendations 
REFERENCES 
 
Coppes, RP, A Meter, SP Latumalea, AF Roffel, HH Kampinga, 2005, Defects in Muscarinic 
Receptor-Coupled Signal Transduction in Isolated  Parotid Gland Cells After in Vivo Irradiation:   
Evidence for a Non-DNA Target of Radiation, Br J Cancer, 92:539-46. 
 
Fajardo, L, M Berthrong, R Anderson, 2001, Radiation Pathology, Oxford University Press, 
Oxford England. 
 
Fajardo, LF and JR Stewart, 1973, Pathogenesis of Radiation-Induced Myocardial Fibrosis, Lab 
Invest, 29:244-257. 
 
Gavin, PR and EL Gillette, 1982, Radiation Response of the Canine Cardiovascular System, 
Radiat Res, 90:489-500. 
 
Giralt, S, W Bensinger, M Goodman, D Podoloff, J Eary et al., 2003, 166Ho-DOTMP Plus 
Melphalan Followed by Peripheral Blood Stem Cell Transplantation in Patients with Multiple 
Myeloma:  Results of Two Phase 1-2 Trials, Blood, 102:2684-2691. 
 
Hall, EJ, 2000, Radiobiology for the Radiologist (5th edition), Lippincott Williams & Wilkins, 
Philadelphia Pa. 
 
Joiner, MC, B Marples, P Lambin, SC Short, I Turesson, 2001, Low-Dose Hypersensitivity:  
Current Status and Possible Mechanisms, Int J Radiat Oncol Biol Phys, 49:379-89. 
 
Marples, B, BG Wouters, SJ Collis, AJ Chalmers, MC Joiner, 2004, Low-Dose Hyper-
Radiosensitivity: A Consequence of Ineffective Cell Cycle Arrest of Radiation-Damaged G -
2
Phase Cells, Radiat Res, 161:247-55. 
 
McChesney, SL, EL Gillette, BE Powers, 1989, Response of the Canine Lung to Fractionated 
Irradiation:  Pathologic Changes and Isoeffect Curves, Int J Radiat Oncol Biol Phys, 16(1):125-
32. 
 
Moll, S, V Nickeleit, J Mueller-Brand, F Brunner, H Maecke, M Mihatsch, 2001, A New Cause 
of Renal Thrombotic Microangiopathy:  Yttrium 90-DOTATOC Internal Radiotherapy, Am J 
Kidney Dis, 37:847-851. 
 
Molteni, A, JE Moulder, EF Cohen, WF Ward, BL Fish et al., 2000, Control of Radiation-
Induced Pneumopathy and Lung Fibrosis by Angiotensin-Converting Enzyme Inhibitors and an 
Angiotensin II Type 1 Receptor Blocker, Int J Radiat Biol, 76(4):523-532.  
 
Moulder, JE and BL Fish, 1989, Late Toxicity of Total Body Irradiation with Bone Marrow 
Transplantation in a Rat Model, Int J Radiat Oncol Biol Phys, 16 (6):1501-9. 
 
Moulder, JE, BL Fish, EP Cohen, 1998, Angiotensin II Receptor Antagonists in the Treatment 
and Prevention of Radiation Nephropathy, Int J Radiat Biol, 73(4):415-21. 
9 
 Contains Nonbinding Recommendations 
 
Perez, CA, LW Brady, EC Halperin, RK Schmidt-Ullrich, (eds), 2004, Principles and Practice of 
Radiation Oncology (4th edition), Lippincott Williams & Wilkins, Philadelphia Pa.  
 
Prescott, DM, PJ Hoopes, DE Thrall, 1990, Modification of Radiation Damage in the Canine 
Kidney by Hyperthermia:  A Histologic and Functional Study, Radiat Res, 124(3):317-25. 
 
Tubiana, M, J Dutreix, A Wambersie, 1990, Radiobiologie, Hermann, Paris France, Translated 
by DR Bewley as Introduction to Radiobiology, Taylor and Francis, New York. 
 
Yaes, R, 1992, Radiation Damage to the Kidney, Advances in Radiation Biology, 15:1-35. 
 
 
  10
  Contains Nonbinding Recommendations 
GLOSSARY 
 
Acute Radiation Syndrome  The symptoms, when taken together, characterize a person 
suffering from the effects of intense radiation.  The effects occur within hours or days. 
 
Dose Fractionation  A method of administering therapeutic radiation in which relatively 
small doses are given daily or at longer intervals. 
 
Early Effects (of radiation exposure)  Effects that appear within 60 days of an acute 
exposure. 
 
Late Effects (of radiation exposure)  Effects that appear 60 days or more following an acute 
exposure. 
 
Radiation Absorbed Dose  The energy imparted to matter by ionizing radiation per unit mass 
of irradiated material at the place of interest.  In SI units, the unit of radiation absorbed dose is 
the Gray (Gy), which is 1 J/Kg.  One Gy equals 100 rads. 
 
Radionuclide  Any radioactive isotope of an element. 
 
Radiosensitivity  Relative susceptibility of cells, tissues, organs, organisms, or any living 
substance to the injurious action of radiation.  Radiosensitivity and its antonym, radioresistance, 
are currently used in a comparative sense, rather than in an absolute one. 
 
Therapeutic Radiopharmaceutical  A radiopharmaceutical drug product or radiobiological 
that is intended for use in the treatment of cancer in humans and that contains a radioactive 
isotope that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear 
radiation. The isotopes used in therapeutic radiopharmaceuticals are usually beta emitters, 
whereas the isotopes used in diagnostic radiopharmaceuticals are gamma emitters.  Therapeutic 
radiopharmaceuticals are given in much higher activities and deliver much higher radiation 
absorbed doses than diagnostic radiopharmaceuticals. 
 
Tracer Dose  The lowest dose based on the as-low-as-reasonably-achievable principle that 
will provide a diagnostic image. 
 
 
11