The document discusses the importance of body weight measurements in toxicology studies, factors that can affect body weight and growth, how to interpret body weight data, and potential artifacts that can confound the assessment of body weight effects such as ensuring test diets are balanced and controls are appropriate. It provides guidance on evaluating whether observed body weight changes are treatment-related and adverse.
The effect of high-fat versus high-carb diet on body composition in strength-...RefoRefaat
Low-fat, high-carb (LFHC) and low-carb, high-fat (LCHF) diets change body composition as a consequence of the reduction of body fat of overweight persons. The
aim of this study is the assessment of the impact of LFHC and LCHF diets on body
composition of men of a healthy body mass who do strength sports while maintaining the appropriate calorific value in a diet and protein intake. The research involved
55 men aged 19–35, with an average BMI of 24.01 ± 1.17 (min. 20.1, max. 26.1). The
participants were divided into two groups following two interventional diets: highfat diet or high-carb diet, for 12 weeks. The body composition of the participants
Do you know that studies have shown that probiotics goes beyond gut health? Learn more from Dr. Anders Henriksson, Principal Application Specialist through his presentation at the Food for Health Conference held in conjunction with UMass 100th anniversary.
Bariatric surgery is one of the most effective treatments of obesity in adults. Unlike many drugs prescribed for the treatment of obesity, bariatric surgery has a broad range of effects, including physiological impact on the gastrointestinal tract and gut microbiota.
In this final installment of our Obesity 2020 webinar series, Dr. Lee Kaplan discusses late-breaking research and reviews various mechanisms of action of bariatric and metabolic surgery and how they affect the regulation of energy balance and metabolic function.
Learn how the Prolon Fasting Mimicking Diet produces all of the benefits of fasting for health, disease prevention and treatment - without the typical challenges associated with pure water fasting
The effect of high-fat versus high-carb diet on body composition in strength-...RefoRefaat
Low-fat, high-carb (LFHC) and low-carb, high-fat (LCHF) diets change body composition as a consequence of the reduction of body fat of overweight persons. The
aim of this study is the assessment of the impact of LFHC and LCHF diets on body
composition of men of a healthy body mass who do strength sports while maintaining the appropriate calorific value in a diet and protein intake. The research involved
55 men aged 19–35, with an average BMI of 24.01 ± 1.17 (min. 20.1, max. 26.1). The
participants were divided into two groups following two interventional diets: highfat diet or high-carb diet, for 12 weeks. The body composition of the participants
Do you know that studies have shown that probiotics goes beyond gut health? Learn more from Dr. Anders Henriksson, Principal Application Specialist through his presentation at the Food for Health Conference held in conjunction with UMass 100th anniversary.
Bariatric surgery is one of the most effective treatments of obesity in adults. Unlike many drugs prescribed for the treatment of obesity, bariatric surgery has a broad range of effects, including physiological impact on the gastrointestinal tract and gut microbiota.
In this final installment of our Obesity 2020 webinar series, Dr. Lee Kaplan discusses late-breaking research and reviews various mechanisms of action of bariatric and metabolic surgery and how they affect the regulation of energy balance and metabolic function.
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Dietary Strategies for Weight Loss MaintenanceMARKETDIGITALBN
Weight regain after a successful weight loss intervention is very common. Most studies
show that, on average, the weight loss attained during a weight loss intervention period is not
or is not fully maintained during follow-up. We review what is currently known about dietary
strategies for weight loss maintenance, focusing on nutrient composition by means of a systematic
review and meta-analysis of studies and discuss other potential strategies that have not been studied
so far. Twenty-one studies with 2875 participants who were overweight or obese are included in
this systematic review and meta-analysis
Introduction: Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy. Methods: Rats were treated twice daily with pantoprazole sodium (PTZ; 10 mg/kg peroral) or vehicle for a total of 10 days. In some experiments, Diclofenac sodium (DCF; 9 mg/kg) or vehicle was administered orally twice daily for the final 5 days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12 hours after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. Results: The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ. Conclusions: This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit, serum albumin, serum total protein levels and IP alteration, known to occur in patients receiving NSAIDs. Additionally, this paper provides yet another evidence for PPI induced exacerbation of NSAID enteropathy.
Animal Model Selection, Study Design and Current Trends in Preclinical Obesit...InsideScientific
During this presentation, Dr. Fred Beasley gives a broad-level overview of the factors to consider when deciding on an appropriate preclinical rodent model for studying obesity and its treatments. It features an overview of trends in obesity and associated illnesses, and the role of pharmacological intervention. Dr. Beasley discusses criteria for establishing a study’s aims and review commonly used rodent models obesity, addressing both genetically inherited and diet-induced obesity. The webinar concludes with additional considerations for improving your study design.
Key topics include…
- An introduction to the role of pharmacological intervention in treating obesity
- A guide to establishing study aims for obesity research
- An overview of commonly used rodent obesity models (diet and genetic)
- Additional considerations for obesity research study design
Key methods reviewed include…
Pharmacotherapy, diet induced obesity, Western-style diet, monogenic obese rodents, polygenic obese rodents, NAFLD activity score
Now a days everybody wants evidence or proof for any purpose.so govt.of india introduces AYUSH research portal for the devalopment and taking awareness regarding ayurveda where it consists of clinical trial and pre-clinical trial data.
Effects of milk supplementation with conjugated linoleic acid (isomers cis-9, trans-11 and trans-10, cis-12) on body composition and metabolic syndrome components
Dietary Strategies for Weight Loss MaintenanceMARKETDIGITALBN
Weight regain after a successful weight loss intervention is very common. Most studies
show that, on average, the weight loss attained during a weight loss intervention period is not
or is not fully maintained during follow-up. We review what is currently known about dietary
strategies for weight loss maintenance, focusing on nutrient composition by means of a systematic
review and meta-analysis of studies and discuss other potential strategies that have not been studied
so far. Twenty-one studies with 2875 participants who were overweight or obese are included in
this systematic review and meta-analysis
Introduction: Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy. Methods: Rats were treated twice daily with pantoprazole sodium (PTZ; 10 mg/kg peroral) or vehicle for a total of 10 days. In some experiments, Diclofenac sodium (DCF; 9 mg/kg) or vehicle was administered orally twice daily for the final 5 days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12 hours after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. Results: The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ. Conclusions: This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit, serum albumin, serum total protein levels and IP alteration, known to occur in patients receiving NSAIDs. Additionally, this paper provides yet another evidence for PPI induced exacerbation of NSAID enteropathy.
Animal Model Selection, Study Design and Current Trends in Preclinical Obesit...InsideScientific
During this presentation, Dr. Fred Beasley gives a broad-level overview of the factors to consider when deciding on an appropriate preclinical rodent model for studying obesity and its treatments. It features an overview of trends in obesity and associated illnesses, and the role of pharmacological intervention. Dr. Beasley discusses criteria for establishing a study’s aims and review commonly used rodent models obesity, addressing both genetically inherited and diet-induced obesity. The webinar concludes with additional considerations for improving your study design.
Key topics include…
- An introduction to the role of pharmacological intervention in treating obesity
- A guide to establishing study aims for obesity research
- An overview of commonly used rodent obesity models (diet and genetic)
- Additional considerations for obesity research study design
Key methods reviewed include…
Pharmacotherapy, diet induced obesity, Western-style diet, monogenic obese rodents, polygenic obese rodents, NAFLD activity score
Now a days everybody wants evidence or proof for any purpose.so govt.of india introduces AYUSH research portal for the devalopment and taking awareness regarding ayurveda where it consists of clinical trial and pre-clinical trial data.
Effects of milk supplementation with conjugated linoleic acid (isomers cis-9, trans-11 and trans-10, cis-12) on body composition and metabolic syndrome components
Deploying Automated Workstreams and Computational Approaches for Generation of Toxicity Data Used for Hazard Identification, by Robert T. Dunn, II, Ph.D., DABT
04 May 2015Page 1 of 28ProQuestIntegrating Fundamental Conce.docxmercysuttle
04 May 2015
Page 1 of 28
ProQuest
Integrating Fundamental Concepts of Obesity and Eating Disorders: Implications for the Obesity Epidemic
Author: Macpherson-Sánchez, Ann E, EdD, MNS
ProQuest document link
Abstract: Physiological mechanisms promote weight gain after famine. Because eating disorders, obesity, and dieting limit food intake, they are famine-like experiences. The development of the concept of meeting an ideal weight was the beginning of increasing obesity. Weight stigma, the perception of being fat, lack of understanding of normal growth and development, and increased concern about obesity on the part of health providers, parents, and caregivers have reinforced each other to promote dieting. Because weight suppression and disinhibition provoke long-term weight increase, dieting is a major factor producing the obesity epidemic. The integrated eating disorder-obesity theory included in this article emphasizes that, contrary to dieters, lifetime weight maintainers depend on physiological processes to control weight and experience minimal weight change.
Links: Linking Service
Full text: Headnote
Physiological mechanisms promote weight gain after famine. Because eating disorders, obesity, and dieting limit food intake, they are famine-like experiences. The development of the concept of meeting an ideal weight was the beginning of increasing obesity. Weight stigma, the perception of being fat, lack of understanding of normal growth and development, and increased concern about obesity on the part of health providers, parents, and caregivers have reinforced each other to promote dieting. Because weight suppression and disinhibition provoke long-term weight increase, dieting is a major factor producing the obesity epidemic. The integrated eating disorder-obesity theory included in this article emphasizes that, contrary to dieters, lifetime weight maintainers depend on physiological processes to control weight and experience minimal weight change. (Am J Public Health. 2015;105:e71-e85. doi:10. 2105/AJPH.2014.302507)
Since 1960, the Centers for Disease Control and Prevention has done periodic surveys of representative samples of the US population, which include measured heights and weights.1 From the 1960 to 1962 to the 1976 to 1980 measurement periods, there was little change in population weight. However, the next survey (1988-1994) showed increases in body mass index (BMI; defined as weight in kilograms divided by the square of height in meters [kg/m2]) that were unanticipated and inexplicable.2 Most of the increase occurred in those with BMI of 30 or greater.3 In 2006, a prominent Centers for Disease Control and Prevention researcher expressed frustration with her incapacity to explain why this happened.2
Losing weight and recuperating from that weight loss is part of the biological heritage of every human being.4-6 However, in the past 70 years, self-induced famine (dieting to achieve and maintain a lower weight)7 became the socie ...
FDA 2013 Clinical Investigator Training Course: Clinical Discussion of Specia...MedicReS
FDA 2013 Clinical Investigator Training Course: Clinical Discussion of Special Populations
Ryan P. Owen, Ph.D.. Office of Clinical Pharmacology, Office of Translational Sciences,CDER
The Okinawa Flat Belly Tonic is a new one of a kind weight loss “tonic” supplement. It helps men and women burn fat fast using a simple 20-second Japanese tonic. IF THAT TONIC DOES NOT WORK AS GIVEN YOUR VALUABLE MONEY WILL REFUND WITH IMMEDIATE EFFECT.
MODULE 1
Introduction to nutrition in emergencies
PART 2: TECHNICAL NOTES
The technical notes are the second of four parts contained in this module. They provide an introduction to nutrition in emergencies. The technical notes are intended for people involved in nutrition programme planning and implementation. They provide technical details, highlight challenging areas and provide clear guidance on accepted current practices. Words in italics are defined in the glossary.
These technical notes are based on the other HTP modules as well as the following references and related Sphere standards in the box below:
• Lancet Nutrition Series, 2008. http://www.thelancet.com/series/maternal-and-child-undernutrition
• Integrated Phase Classification system, www.ipcinfo.org
• SMART guidelines, www.smartmethodology.org
• Young, H., A. Borrel, Hollard, D. & Salama, P. (2004). Public nutrition in complex emergencies. The Lancet, 364: 1899-909. http://www.who.int/hac/techguidance/training/predeployment/Public%20health%20nutrition%20in%20complex%20emergencies.pdf
• Young & Jaspars (2006). The Meaning and Measurement of Malnutrition in Acute Emergencies. Network Paper Number 56. London: ODI. http://www.ipcinfo.org/attachments/Meaning_and_measurement_of_acute_malnutrition_in_emergencies.pdf
• Sphere Handbook, 2011. http://www.sphereproject.org/component/option,com_docman/task,cat_view/gid,70/Itemid,203
• IASC Global Nutrition Cluster, http://oneresponse.info/globalclusters/nutrition/Pages/default.aspx
• Emergency Nutrition Network publication, Field Exchange. www.ennonline.net/fex
• United Nations Office for the Coordination of Humanitarian Affairs, http://www.unocha.org
• Nutrition Information in Crisis Situations, NICS, http://www.unscn.org/en/publications/nics/
• Famine Early Warning System Network (FEWS NET) , http://www.fews.net/Pages/default.aspx
Sphere standards
Food security and nutrition assessment standard 1: Food Security
Where people are at increased risk of food insecurity, assessments are conducted using accepted methods to understand the type, degree and extent of food insecurity, to identify those most affected and to define the most appropriate response.
Food security and nutrition assessment standard 2: Nutrition
Where people are at increased risk of undernutrition, assessments are conducted using internationally accepted methods to understand the type, degree and extent of undernutrition and identify those most affected, those most at risk and the appropriate response.
Infant and young child feeding standard 1: Policy guidance and coordination
Safe and appropriate infant and young child feeding for the population is protected through implementation of key policy guidance and strong coordination.
Infant and young child feeding standard 2: Basic and skilled support
Mothers and caregivers of infants and young children have access to timely and appropriate feeding support that minimises risks and optimises nutrition, healt
1. Body Weight in Toxicology Studies
Dr R B Cope BVSc BSc(Hon 1) PhD cGLPCP DABT ERT
24/01/2013 Dr R B Cope 1
2. Learning Objectives
• To understand what body weight measurements are used in
toxicology studies
• Understand the factors affecting body weight and growth
• Understand the potential artifacts affecting body weight and
growth measurements
• Understand the critical design factors pertaining to the design
of diets for toxicology studies
• The importance of control data and the types of control data
available
• Understand the factors involved in determining treatment-
related and adverse effects
• Understand the factors involved in determining abnormal
thresholds for body weight and growth in toxicology studies
24/01/2013 Dr R B Cope 2
4. Common Parameters Measured
• Growth (body weight change over time)
• Absolute body weight
• Food consumption relative to body weight
• Efficiency of food utilization (body weight gain per 100 g of
food consumed)
• Cumulative food consumption (total food consumed since the
start of the study divided by the days on study)
• Cumulative food consumption relative to body weight
(cumulative daily food consumption divided by average body
weight)
24/01/2013 Dr R B Cope 4
9. Interpretation of Body Weight and Body Weight Gain
in Repeat Dose Studies
• Body weight, and in particular growth (body weight gain) is
often a particularly sensitive general endpoint in toxicology
• In theory, long term changes in body weight are dependent
upon:
– Genetic potential for growth
• Hopefully equivalent across study groups because of
inbred/line-bred strains and random allocation to
groups
• Critical that the same strain should be used in all
experimental groups
24/01/2013 Dr R B Cope 9
10. Interpretation of Body Weight and Body Weight Gain
in Repeat Dose Studies
• In theory, long term changes in body weight are dependent
upon:
– Stage of development span over which the measurements
are taken (e.g. juvenile to adult, mature adult only etc..)
• Critical that the same batch of animals (same
generation, same age range, same rearing etc.) be used
across all experimental groups
• Critical that there is genuinely random allocation to
treatment group
24/01/2013 Dr R B Cope 10
11. Interpretation of Body Weight and Body Weight Gain
in Repeat Dose Studies
• In theory, long term changes in body weight are dependent
upon:
– Balance between caloric intake and caloric expenditure
over the long term
24/01/2013 Dr R B Cope 11
12. Interpretation of Body Weight and Body Weight Gain
in Repeat Dose Studies
• Some factors that need to be considered are:
– Energy demand
• Room temperature
• Individually or group housed (heat loss)
• Presence of a hair coat and type of hair coat
– Food palatability
– Dietary caloric density
– Food availability
24/01/2013 Dr R B Cope 12
13. Interpretation of Body Weight and Body Weight Gain
in Repeat Dose Studies
• Some factors that need to be considered are:
– Injuries that may inhibit eating/drinking
– Nutrient deficiencies induced by the test article or due to
dilution of essential nutrients by high concentrations of
the test article
– Capacity and opportunity to exercise
– Neurological/neurobehavioral effects of the test article
– General ill thrift
• Rodents that are a little sick tend not to eat become mildly
hypothermic quickly (high metabolic rate per unit volume)
become less likely to eat become more hypothermic etc.
24/01/2013 Dr R B Cope 13
14. Interpretation of Body Weight and Body Weight Gain
in Repeat Dose Studies
• Some factors that need to be considered are:
– Test article has the capacity to alter metabolic rate
• Most notably, to disturb the hypothalamic-pituitary-
thyroid axis
– Test article has the capacity to increase or decrease heat
loss (e.g. peripheral vasoconstrictors/vasodilators)
24/01/2013 Dr R B Cope 14
15. Guidance from the FDA Redbook:
• When the test substance has no caloric value and constitutes a substantial
amount of the diet (e.g., more than 5%), both caloric and nutrient
densities of the high dose diet would be diluted in comparison to the diets
of the other groups. As a consequence, some high dose animals may
receive higher test substance doses than expected because animals fed
such diluted diets ad libitum may eat more than animals in other dosed
groups to compensate for the differences in energy and nutrient content
of the high dose diets. Such circumstances make it especially important
that feed consumption of these animals be as accurately and closely
monitored as possible in order to determine whether changes observed
could be due to overt toxicity of the test substance or to a dietary
imbalance. To further aid in this assessment, two control groups can be
used; one group would be fed the undiluted control diet and a second
group would be fed the control diet supplemented with an inert filler (e.g.,
methylcellulose) at a percentage equal to the highest percentage of the
test substance in the diet.
24/01/2013 Dr R B Cope 15
16. Guidance from the FDA Redbook:
• When the vehicle for the test substance is expected to have caloric and/or nutritional values,
which are greater than that of the control ration, an adjustment in the caloric and/or
nutritional components may be necessary.
• When administration of the test substance is expected to have an effect on feed intake
because of its unpleasant taste or texture, other feeding regimens or experimental designs
may be necessary.
• When the test substance interferes with the absorption of nutrients, leading to nutritional
deficiencies or changes in nutrient ratios, this can confound assessment of the toxicological
endpoints under consideration. For example, fat soluble vitamins may preferentially partition
with a mineral oil or fat substitute which is largely unabsorbed, such that a potential
deficiency in these vitamins may result. This potential may be eliminated by additional
nutrient fortification of the feed for those groups receiving the test substance. Appropriate
levels of nutrient fortification should be determined experimentally.
24/01/2013 Dr R B Cope 16
17. Guidance from the FDA Redbook:
• If the above guidance has not been adhered to, it
makes it extremely difficult to interpret the findings
of a study and to determine what effects are
adverse, what effects are test article-related and
what effects are artifact
• If the study does not adhere to these guidelines it
should be rejected and a better study performed
24/01/2013 Dr R B Cope 17
18. Common Artifacts Affecting Growth
and Body Weight in Toxicology Studies
• High levels of the test article are used in the experimental
diets which distorts their nutritional characteristics and caloric
density
– Control diet and test diets are not isocaloric and
isonutritive
– Common things that I personally seen which are not
directly related to the pathophysiology of the test article:
• Iron deficiency due to dilution of the diet formulation
by high levels of the test article
• B-group vitamin deficiencies due to dilution of the diet
formulation by high levels of the test article
Remember: toxicology studies often use young (6 week old) rapidly growing
animals tat have a high nutritional demand. Under these circumstances, the effects
of dietary deficiencies are often more pronounced than in adult animals
24/01/2013 Dr R B Cope 18
19. Common Artifacts Affecting Growth
and Body Weight in Toxicology Studies
• High levels of the test article are used in the experimental
diets which distorts their nutritional characteristics and caloric
density
– Control diet and test diets are not isocaloric and
isonutritive
– Common things that I personally seen which are not
directly related to the pathophysiology of the test article:
• Iron deficiency due to dilution of the diet formulation
by high levels of the test article
• B-group vitamin deficiencies due to dilution of the diet
formulation by high levels of the test article
Remember: toxicology studies often use young (6 week old) rapidly growing
animals tat have a high nutritional demand. Under these circumstances, the effects
of dietary deficiencies are often more pronounced than in adult animals
24/01/2013 Dr R B Cope 19
20. Common Artifacts Affecting Growth
and Body Weight in Toxicology Studies
• Not changing the cages or water bottles of all the experimental groups on
the same day in relation to the measurement of body weight
• Leaving the water bottles out of the cages before performing body weight
measurements
• Using different scales with different calibrations to measure different
experimental groups
24/01/2013 Dr R B Cope 20
21. Common Artifacts Affecting Growth
and Body Weight in Toxicology Studies
• Different experimental groups housed in different rooms or in different
parts of the same room – different environmental conditions (notably
temperature, ventilation, noise levels etc.)
• Different experimental groups subjected to different lighting patterns
• Contaminants in the dietary formulations (notably aflatoxins and other
mycotoxins in corn-based AIN diets)
• Unexpected contaminants in the test article
• Changing the test article batch half-way through the study
24/01/2013 Dr R B Cope 21
22. Common Artifacts Affecting Growth
and Body Weight in Toxicology Studies
• Control and experimental diets stored under different conditions
• Mixing and batch errors with diets (should always have analytical data on
the concentration of the test article in the final formulated diets and
stability data regarding the test article once it is incorporated in the diet)
• Lack of retention samples – makes it really hard to figure out what when
wrong if you can’t go back and analyze the test article or the test diets
• Test article tested is not the same as the test article being registered
Note: it is very common with new chemicals that the initial tox testing is performed on
relatively impure substances and the later tox testing is performed on progressively
more pure preparations of the substance. This can make it difficult at times to work out
what specifically is causing the effects and how these relate to the same substance
produced by different suppliers or with different industrial grades of the same
substance. Petroleum solvents are notorious for this problem
24/01/2013 Dr R B Cope 22
23. The Importance of Control Data
in Assessing Body Weight and Growth
• The control data that should (ideally) be available:
– Historical growth rate curve (with SD/95% CI) for the particular species
and strain from the animal supplier
– Historical growth rate curve (with SD/95% CI) for the particular species
and strain from the experimental facility using the same control diet
formulation
– Data from the negative control group in the study
– Feed consumption data from the control and experimental groups
– Analytical data on diet/water impurities (part of GLP)
24/01/2013 Dr R B Cope 23
24. Interpreting Body Weight and Growth Data
• Is the effect related to treatment (i.e. cause and effect)?
A difference is less likely to be treatment-related if:
– There is no obvious dose response (provided that there is appropriate
dose spacing; body weight and growth effects are almost always
statistically continuous data)
– The effect is due to one or more animals that could be considered
outliers
– Measurement is inherently imprecise (i.e. not repeatable)
– Any effect is within normal biological variation (i.e. within ± 3 SD of the
mean assuming normal distribution) based on relevant historical
control values
– There is a lack of biological plausibility – i.e. is there a likely mode of
action for the effects on weight and growth? Are the effects similar to
other substances in the same chemical class?
– There are artifacts in the experimental design or inadequate controls
(control artifacts)
24/01/2013 Dr R B Cope 24
25. Interpreting Body Weight and Growth Data
• Is the observe effect adverse?
A difference is less likely to be adverse if:
– There is no alteration in general function of the animal or any relevant
organs/tissues
– There is evidence of transiency or adaptation e.g. short period of
mildly decreased growth/weight loss while adapting onto the diet
followed by a recovery (quite common)
– The severity is less than the threshold of concern (see below)
– The effects are isolated or independent from other adverse effects e.g.
body weight/growth change does not appear to affect survival or
functioning in the long-term
– The effect is peculiar to the particular species or strain
– The effect is not a precursor to other adverse effects
– The effect on body weight/growth is secondary to another effect e.g.
reduced palatability, test article induces pain when eaten etc..
24/01/2013 Dr R B Cope 25
26. Interpreting Body Weight and Growth Data
• So what is the threshold of concern for body weight and
growth?
– In reproductive/developmental studies any statistically
significant reduction in body weight and growth that is
maintained over the course of development is generally
adverse, even if not associated with specific adverse
changes to other parameters
– Reduced body weight or growth in the pre-weaning phase
of development is almost always adverse and of concern
24/01/2013 Dr R B Cope 26
27. Interpreting Body Weight and Growth Data
• So what is the threshold of concern for body weight and
growth?
– Small changes (statistically significant) which remain within
the normal range of relevant historical control data are
likely not adverse
– Changes outside of the normal range that are consistent
over time (i.e. repeatable over time) are likely adverse
– Changes that are associated with abnormal feed
consumption are potentially adverse
24/01/2013 Dr R B Cope 27
28. Maximum Tolerated Dose
• Definition:
– highest dose of a xenobiotic that will produce the desired effect
without unacceptable toxicity (excessive deaths)
– Typically in toxicology studies, the threshold for the MTD is the dose is
expected to produce ≤ 10% decrease growth compared with control
animals in a chronic near life-time study based on data derived from a
sub-chronic (90 day) study
• There is evidence to suggest that a > than 10% decrease in growth will
result in distortion of the results of chronic studies (notably
carcinogenesis) as well as producing adverse effects are associated with
the effects of decreased growth/weight loss rather than the test article
per se.
• Suggests that a 10% decrease in growth or body weight in a 90 day study is
more than likely to be adverse (controversial)
24/01/2013 Dr R B Cope 28
29. Feed/Water Consumption
• Requirements
– If the test article is administered in the food, food
consumption should be measured at the same interval as
body weights
– If the test article is administered in the water, water
consumption should be measured at the same interval as
body weights
– It is impossible to accurately estimate the dose unless you
have the above data
• There is generic data on feed consumption for
experimental species that can be used as a last resort,
but often this is HIGHLY inaccurate and can lead to
serious under or over estimation of the doses
24/01/2013 Dr R B Cope 29
30. Feed Consumption
• Under most circumstances, feed consumption parallels
growth and growth rate.
• Under most circumstances, water consumption parallels
growth, growth rate and feed consumption
– Renal disease – reduced or increased depending on the type and stage
of the disease
– Diabetes mellitus
– Level of salt in the diet
24/01/2013 Dr R B Cope 30