Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in
Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Adverse versus non-adverse – the role of
adaptation
John R Foster FRCPath,
ToxPath Sciences Ltd, Congleton, United Kingdom
Hosted by:
European Society of Toxicologic Pathology
Co-sponsored by: British Society of Toxicological Pathology, French Society of Toxicological Pathology and Society of Toxicologic Pathology
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Adaptive versus adverse?
•
•
•
•
“Adaptive” and “adverse” changes are not mutually
exclusive conditions!
An adaptive change permits an organism to respond to
an environmental change and is always to the benefit of
the organism – not always desirable!
An adaptive change can sometimes result in a change in
the function of the organ – smoking-induced mucous
metaplasia of bronchial mucosa
What can be a beneficial, adaptive change acutely, can
develop into an adverse change in the longer term.
page 2
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
When adaptive becomes adverse
• An adaptive change can develop into an adverse one if environmental
conditions become so altered as to require the change for the survival of
the organism
• The adverse effect normally develops secondarily to, or as a progression
of, the initial adaptive change
• An examples of this is alcohol-induced liver damage:
–
–
–
–
alcohol-induced increased clearance
Hepatic damage
Hepatic fibrosis
Hepatic cirrhosis
– Death.
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Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Adaptation is homeostasis in action – a normal
response!
Correcting
mechanism
Stress
Correcting
mechanism
Return to
optimum
Stress
Return to
optimum
Optimum state
Correcting
mechanism
Correcting
mechanism
The system is one in dynamic equilibrium
Page 4
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Normal, adaptation, and pathology
Response to the environment
Homeostasis
Normal variability
Stable change
Unstable change
Adaptation
(Non-adverse)
= represents amount of energy required to maintain the state
Pathology
(Adverse)
Page 5
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Two examples of “Adaptive” changes
• Liver hypertrophy/hyperplasia
–
–
–
–
Histopathology
Biochemical changes
Serum biochemistry/functional changes
Biomarkers
• Nasal toxicity to irritants
– Histopathology
– Function?
Page 6
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Liver as an organ designed for interacting with
the environment
 Front line for chemicals entering body through food.
 Has developed processes through evolution to deal with xenobiotics
 Shows adaptive changes to increased metabolic demand – liver growth,
hypertrophy/hyperplasia
 Liver growth is one of the most common response to xenobiotics.
 It is the normal adaptation to its environment but………..
 Can show adverse changes to overtly toxic doses of xenobiotics - necrosis
and fibrosis.
Page 7
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
What happens at high doses of chemicals that cause
liver enlargement at lower doses?
• Virtually all chemicals that cause only liver growth/hypertrophy/
hyperplasia at low doses will induce degeneration at higher doses.
• Clearly the presence of degeneration is an adverse response
• It is accepted that functional replacement may not be total, and fibrotic
reactions that occur in this case result in permanent loss of function.
• Under these circumstances the changes observed are clearly adverse and
a NOAEL is not present at dose levels where these effects occur.
Page 17
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
What are the accompanying signs of
saturation and toxicity in the liver
 Histopathology - zonal necrosis, increased apoptosis/single cell necrosis,
excess fatty accumulation, inflammatory cells
 Clinical biochemistry - increased release of liver enzymes into the plasma –
transaminases, ALP, GGT etc
 Decreased plasma albumin and g-globulins
Page 19
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Current approaches to defining increased liver
weight as adverse
•
In the presence of histopathology, additional to hepatocellular hypertrophy,
the increased liver weight is adverse.
•
The presence of statistically significant changes in serum parameters indicative of
cytotoxicity, ALT ↑, AST ↑, ALP ↑, bilirubin ↑, albumin ↓, g-globulins ↓
•
In the absence of the above, the definition of adverse, based upon increased
liver weight, seems to be dependent upon the magnitude of response:
– <10% increased weight not associated with liver cancer in rodents whereas ≥50% was
associated with cancer (Carmichael et al 1997).
– NTP database showed that ≥50% increase in liver weight was associated with cancer in
rodents (Haseman et al 1997)
– Liver enlargement ≥ 40% was associated with hepatic neoplasia in C57Bl/10j mice
(Greaves 1996)
– Pesticide Safety Directorate/ACP guidance document suggested that increases in liver
weight in rodents of <10% were considered to be non-adverse, while increases of >10%
were interpreted as being potentially adverse (Andrew 2005)
http://www.pesticides.gov.uk/Resources/CRD/MigratedResources/Documents/A/ACP_Paper_on_the_interpretation_of_Liver_Enlargement.pdf
Page 10
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Conclusions: Liver enlargement alone
• Regulatory agencies in EU regard ≥20% increase in liver weight as adverse,
irrespective of duration of study showing the effect and of the species
showing it.
• Why?
• This is a dogmatic stance that lacks sound, scientific, support.
• In the absence of additional evidence of cytotoxicity (serum enzymes etc.)
hypertrophy alone should be regarded as non-adverse and should be used
to set a NOAEL.
– At dose levels that induce additional cytotoxicity, chronic induction of
regenerative cell replication would occur – a clear risk factor for chronic
toxicity/carcinogenicity.
Page 11
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Industrial chemical – furfuryl alcohol
• Large production volume, chemical intermediate
• Eye irritation is limiting in human studies – limited evidence for respiratory
effects in man!
• Male and female F344/N rats and B6C3F mice exposed by inhalation for
6hr/day for 5 days/week for 2 years (NTP TR482 – 1999).
• Non-genotoxic
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14 week study in F344 rats
Male
Female
Exposure (ppm)
0
2
4
8
32
0
2
4
8
32
No examined
10
10
10
10
10
10
10
10
10
10
Squamous metaplasia –
respiratory epithelium
0
0
0
5
10
0
0
0
6
10
Mucous hyperplasia –
respiratory epithelium
0
0
0
7
10
0
0
0
2
9
Squamous metaplasia –
transitional epithelium
0
9
10
10
10
0
9
10
10
10
Degeneration/vacuolation –
olfactory
0
1
4
9
10
0
3
7
10
10
Hyperplasia – olfactory
0
0
1
2
9
0
0
0
2
10
Metaplasia – olfactory
0
0
0
0
2
0
0
0
0
5
Surface exudate – olfactory
0
0
0
0
7
0
0
0
2
10
Inflammation
0
0
0
1
10
0
2
0
3
6
•
•
•
No NOEL but changes ≤8 ppm were all minimal grade and focal (level 2 only)
No effects on food consumption/body weight – no functional effects at or below 8 ppm!
Could 8 ppm be NOAEL?
Page 13
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Two year studies - results
Male
Female
0
2
8
32
0
2
8
32
Suppurative inflammation
3/50
6/50
17/50
44/50
4/49
1/50
5/48
23/49
Hyperplasia – lateral wall
1/50
49/50
50/50
50/50
0/49
39/50
48/48
49/49
Metaplasia – squamous
1/50
1/50
8/50
33/50
0/49
1/50
0/48
24/49
Squamous cell neoplasia
0/50
1/50
1/50
4/50
0/50
0/50
0/50
0/50
Suppurative inflammation
7/50
11/49
27/49
28/50
5/50
12/48
25/49
42/50
Metaplasia – squamous
0/50
6/49
35/49
47/50
1/50
1/48
34/49
46/50
F344 rat
B6C3F1 mouse
•
•
•
•
•
•
NOEL in male rat at 8ppm for neoplasia – combined nasal tumours
No neoplasia in female rat, male or female mouse
No NOEL for non-neoplastic findings but……
Squamous metaplasia
High incidence of low severity (minimal to mild), and focal to level 2 of the nasal passages at 8 ppm and
below!
No effects on survival/food consumption/body weight – no obvious functional deficit!
NOAEL at 8 ppm?
Page 14
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Nasal tissue lesions with furfuryl
alcohol
• In female rat and mice lesions occur early and do not
progress to cancer – can they be considered non-adverse?
• Lesion severities at 8 ppm and below were minimal to mild
grading and focal to level 2 of nasal passages
• Lesions are expected to recover – no recovery study
available.
• Can they be considered an adaptive response as a
consequence of the expected function of the nose in
scrubbing out irritant chemicals?
• Can a NOAEL be set at 8 ppm?
Page 15
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
Summary
• Adaptation is an evolutionary strategy for survival
• Adaptive changes are not necessarily non-adverse
• Decision of “non-adverse” for a change is based upon the
impact of the change on the function of the organ.
• An adaptive change that results in, or leads to, the long
term degeneration of the organ is clearly adverse –
hepatic fibrosis; neoplasia.
• Adaptive changes are not necessarily reversible.
Page 16
Webinar on: “Considerations and Guidance for Adversity Decisions on Pathological Findings in Toxicology and Pathology Reports”
based on presentations given at the 4th International ESTP Expert Workshop in Paris, France, June 08+09, 2015
THANK YOU FOR YOUR ATTENTION
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