Innovative methods for early detection and interpretation of chemical exposure using human biological monitoring.

Health of workers can be affected by the working environment. According to RIVM
4.7% of workers suffer from a work-related disease. This resulted in 6,877,500
missed working days. In addition, 22.3% of all incapacitated workers were due
to a work-related disease. An estimated 4000 deaths per year are work related,
of which 3000 are due to exposure to hazardous chemicals. This is an enormous
burden for workers,
employers, the health care system and society. An early warning system for
(hazardous) chemical exposures and associated biological effects is needed to
prevent diseases due to hazardous chemicals. This is more important as changes
in working conditions result in the rise of new occupational health risks as
emphasized in the European Agency for Safety and Health at Work*s (EU-OSHA*s)
project report on *Methodologies to identify work-related diseases: Review on
sentinel and alert approaches*.

Occupational physicians perform periodic medical examinations (in Dutch,
Preventieve Medische Onderzoeken (PMO)) and periodic occupational health
examinations (in Dutch, Periodiek Arbeidsgezondheidskundig Onderzoek, PAGO)
where often blood analyses are performed. Next to conventional clinical
parameters limited targeted screening of exposures is performed (e.g. benzene,
PAHs, PFAS, etc.). Although this may suffice for known risks, the limitation is
that exposures may go unnoticed, as (hazardous) chemicals not included in a
targeted screening are missed, though these can be the hazardous chemicals
impacting health, while there is a huge number of hazardous chemicals that
hardly can be captured in a targeted screening.

Technologies based on Mass Spectrometry (MS) offer an opportunity to
agnostically screen for the presence of hazardous compounds (non-targetted
screening (NTS)). To aid occupational health professionals, regulatory bodies
and policy makers in i) evaluating risk for workers in a certain environment,
ii) understanding prevalence of chemical exposures among workers, and iii)
identifying emerging chemicals of concern, we propose to link in this project
routine occupational health examinations with an innovative non-targeted
screening (NTS) using innovative metabolomics/exposomics technologies and
computational workflows.

Primary objective(s):
The overall objective of this project is to develop sampling and analytical
methods that allow for the early detection of chemical exposures in the
workplace. The project's goal is to go beyond the current targeted sampling and
analytical approaches focusing on a single component. As exposures in the
workplace often involve multiple known and unknown compounds, measurement
techniques that can scan for many chemicals at the same time have the potential
to play a role in the early detection of (novel) occupational exposures.
Identification of such chemicals will help to identify emerging exposures of
concern within occupational settings.

Secondary Objective(s):
• Developing a computational pipeline to predict possible risks due to
chemicals used at work and possible biotransformation of these chemicals
• Inventory of endogenous metabolites serving as early warning for presence of
toxic compounds
• In case of uncertainty of possible transformation processes, an in-vitro
transformation experiment can be conducted;

We will recruit participants employed by three companies which names will only
be mentioned in the protocol within the Netherlands' chemical industry from
September to December 2024, facilitated by occupational physicians from Arbo
Unie who will conduct medical examinations under the Periodic Occupational
Health Examination (PAGO) program. Due to privacy concerns, we maintain
confidentiality regarding the companies' names and will only share the names
with METC NedMec in the protocol.

Our target study population comprises 400 employees aged 18-67 years,
potentially exposed to hazardous substances. Participants will provide informed
consent, complete a comprehensive questionnaire covering general information,
lifestyle and nutrition habits, and health status, and provide a blood sample
for research purposes.

Following the blood collection process, samples will be dispatched to the
'Exposome Scan Facility' in Leiden for analysis. Utilizing liquid and gas
chromatography coupled with high-resolution mass spectrometry, we aim to detect
and characterize workers' metabolic profiles.

The identified chemicals and their metabolites will be cross-referenced with
existing knowledge on potential health risks. This will be facilitated by
employing a recently developed automated network assembly method for informed
evidence synthesis and the AOP-helpFinder tool to associate chemicals and
metabolites with Adverse Outcome Pathway (AOP) events, enhancing our ability to
assess potential health impacts accurately.

The extent of the burden and risks associated with participation are minimal in
this study. The participants will be asked to follow their normal routines. The
only burden that we ask the participants via informed consent is if they are
willing to donate blood (6 ml) and fill out a short questionnaire for research
purposes. Participants can withdraw their participation in the study at any
point in time during the study.

The benefit of this study is, however, that it has the capacity to take
prevention and early detection of occupational diseases to the next level. An
early warning system for (hazardous) chemical exposures and associated
biological effects is needed to prevent diseases due to hazardous chemicals.
This is more important as changes in working conditions result in the rise of
new occupational health risks as emphasized in the European Agency for Safety
and Health at Work*s (EU-OSHA*s) project report on *Methodologies to identify
occupational diseases: Review on sentinel and alert approaches*. For the
workers who participate in this study, and all other workers in the same field,
this study gives handles to detect occupational exposures early, thereby
preventing or limiting the burden of occupational diseases.