Obesity Clinical Trial
Official title:
Environmental Chemicals That Accumulate in Fat
A crucial factor in evaluating the risk of dioxins, and related endocrine disruptor compounds
(dioxins for short) in the human population is the accumulation of these chemicals in the
human body. Human data on tissue background levels is extremely limited, and there are no
studies in UK populations, although there are several European studies looking at blood
levels of dioxins. Adipose tissue concentrations were 139 ng of TEQ (total dioxin-like
compounds) per kg lipid weight (5.4 ± 4.6 ng of TCDD per kg lipid weight). However, given the
different dietary habits of Japanese populations, compared to European populations, these
estimates may differ considerably from UK values. Thus determining human tissue
concentrations of dioxins is an important issue for assessing the risk to public health from
these compounds, and this information is currently lacking for European populations. This
information will also guide and inform the necessity fro continued measures to reduce the
environmental dioxin levels in the UK.
Aims
Primary outcomes:
1. Investigation of the toxicodynamics of/dioxin distribution in adipose of a morbidly
obese and comparative control population
2. Characterisation of the burden of dioxins in liver and adipose tissue, and the
relationship with blood levels of dioxins, in a UK population
Secondary outcome:
Determining whether bariatric surgery-induced weight loss causes an increase in tissue
concentration of dioxin-like compounds
The primary aims of this study will yield useful information to refine the risk assessment
process for the obese population.
Experimental Methodology This proposal seeks to examine thirty non-obese patients taking
liver (500mg) and adipose tissue (visceral and subcutaneous: 40g each) samples at the time of
gastric/abdominal surgery; and thirty obese patients, taking liver (500mg) and adipose tissue
(visceral and subcutaneous: 40g each) samples at the time of undertaking Roux -en-y bariatric
surgery. Weight and bioimpedance and a food diary will be performed prior to surgery.
A further body weight and bioimpedance will be undertaken at 3, 6, 9 and 12 months from the
obese population. A subcutaneous adipose biopsy will be taken under local anaesthetic from
these individuals at after bariatric surgery (minimum of 10% body weight loss). A record of
weight loss since bariatric surgery will documented with the change in body composition. The
statistical power for seeing an effect of gastroplasty, assuming a coefficient of variation
of TEQ measurements of 75% and an increase in TEQ of two-fold, is 90% at P<0.05 for a
population of thirty individuals.
Should subjects need additional surgery (eg. cholecystectomy, diagnostic laproscopy) either
as a consequence of bariatric surgery or for any other reasons during the 24 month following
initial operation, a liver biopsy and visceral fat biopsy will be taken during the future
surgery. If subjects undergo abdominal wall surgeries (eg. Apronectomy, ventral hernia
repair) in the 24 months following initial bariatric surgery, an subcutaneous fat biopsy will
be taken during the future surgery.
Background A crucial factor in evaluating the risk of dioxins, and related endocrine
disruptor compounds (dioxins for short) in the human population is the accumulation of these
chemicals in the human body. The "half-life" of the prototypical dioxin,
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the human is estimated as ~7 years, as such
accumulation of these chemicals in the body is an important issue. These lipophilic chemicals
accumulate in adipose tissue, and (in a congener-dependent fashion) in the liver, so an
accurate estimation of human body burden requires knowledge of their concentrations in liver,
and adipose tissue. The concentration of these endocrine disruptors in blood is an essential
piece of information for understanding how these chemicals dispose between the organs, and
for calibrating tissue concentrations to the most common measurement of dioxins and in
humans, which is a measurement of dioxins in blood.
However, human data on tissue background levels is extremely limited, and I am unaware of any
studies in UK populations, although there are several European studies looking at blood
levels of dioxins. There is one study in an American population, which features some people
with a history of (presumably occupational) exposure to TCDD, but this was published in 1988,
when background levels were considerably higher. Adipose tissue concentrations were 83 ± 178
ng of TCDD per kg lipid weight. There are three recent studies from Japan, spanning
1999-2007, so these should be indicative of the much lower current background level of dioxin
exposure. Adipose tissue concentrations were 139 ng of TEQ (total dioxin-like compounds) per
kg lipid weight (5.4 ± 4.6 ng of TCDD per kg lipid weight). However, given the different
dietary habits of Japanese populations, compared to European populations, these estimates may
differ considerably from UK values. Thus determining human tissue concentrations of dioxins
is an important issue for assessing the risk to public health from these compounds, and this
information is currently lacking for European populations. This information will also guide
and inform the necessity fro continued measures to reduce the environmental dioxin levels in
the UK.
A further topical issue relates to the body burden of dioxins in obese individuals, since an
increased BMI is associated with increased blood concentration of dioxin and other lipophilic
contaminants, and the impact of weight reduction upon the concentration and amount of dioxins
in the body is unknown. There is the possibility that weight reduction could result in the
release of dioxins from adipose tissue depots, as the adipose tissue is lost, and that the
circulating dioxin levels (and other toxic lipophilic chemicals) could increase if the dioxin
is maintained in the body, or alternatively as adipose tissue is lost dioxins may be
concentrated in the remaining adipose tissue. Although there is some evidence that weight
loss is associated with an increase in some lipophilic contaminants, dioxins have not been
examined to see if these are increased after weight loss. If dioxin concentrations in lipids
increase following weight loss, it will also be useful to evaluate whether those increased
concentrations persist or rapidly equilibrate, and the data from this study may allow some
evaluation of that question as well. The toxicodynamics information will allow estimation and
prediction of what will happen to other lipophilic chemicals in the body.
Aims
Primary outcomes:
1. Investigation of the toxicodynamics of/dioxin distribution in adipose of a morbidly
obese and comparative control population
2. Characterisation of the burden of dioxins in liver and adipose tissue, and the
relationship with blood levels of dioxins, in a UK population
Secondary outcome:
Determining whether bariatric surgery-induced weight loss causes an increase in tissue
concentration of dioxin-like compounds
The primary aims of this study will yield useful information to refine the risk assessment
process for the obese population.
Experimental Methodology This proposal seeks to examine thirty non-obese patients taking
liver (500mg) and adipose tissue (visceral and subcutaneous: 40g each) samples at the time of
gastric/abdominal surgery; and thirty obese patients, taking liver (500mg) and adipose tissue
(visceral and subcutaneous: 40g each) samples at the time of undertaking Roux -en-y bariatric
surgery. Weight and bioimpedance and a food diary will be performed prior to surgery.
A further body weight and bioimpedance will be undertaken at 3, 6, 9 and 12 months from the
obese population. A subcutaneous adipose biopsy will be taken under local anaesthetic from
these individuals after bariatric surgery (minimum of 10% body weight loss). A record of
weight loss since bariatric surgery will documented with the change in body composition. The
statistical power for seeing an effect of gastroplasty, assuming a coefficient of variation
of TEQ measurements of 75% and an increase in TEQ of two-fold, is 90% at P<0.05 for a
population of thirty individuals.
Should subjects need additional surgery (eg. cholecystectomy, diagnostic laproscopy) either
as a consequence of bariatric surgery or for any other reasons during the 24 month following
initial operation, a liver biopsy and visceral fat biopsy will be taken during the future
surgery. If subjects undergo abdominal wall surgeries (eg. Apronectomy, ventral hernia
repair) in the 24 months following initial bariatric surgery, an subcutaneous fat biopsy will
be taken during the future surgery.
Measurement of dioxins and TEQ will be performed with high resolution GC-MS in a laboratory
accredited for working with dioxins, according to ISO17025. The method is validated to have
high sensitivity (necessary for the small volumes of clinical samples) and robust quality
control (essential for analyses of background levels of dioxins), and the analytical team
have extensive experience of using this technology with demanding biological samples. Lipid
content of sampled tissues will also be measured to allow assessment of lipid-adjusted tissue
concentrations for comparison across tissues and blood, as previous work has demonstrated
that these compounds partition across tissues principally on the basis of lipid content.
Statistical analysis of the effect of gastroplasty on dioxin burden and concentrations will
use a conventional repeated measures methodology. Modelling the relationship between tissue
distribution and blood concentrations of dioxins, especially with regard to different
congeners, will be undertaken by Summit Toxicology, who have extensive experience of these
analyses. The data will be evaluated in the framework of a previously-published toxicokinetic
model, and potential congener-specific differences in behaviour will be evaluated.
It is anticipated that initial data analysis will be undertaken comparing the dioxin burden
between the obese and non-obese subjects (per gram tissue on a wet weight and on a
lipid-adjusted basis, and related to lean body mass). The final data analysis will also take
into account the change in dioxins with time associated with loss of body weight/change in
lean body mass, together with the dioxin load in subcutaneous fat tissue before and after
weight loss.
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