**Meet the editor**

Dr. Michael G. Tyshenko holds the McLaughlin Chair in Biological Risk Assessment at the University of Ottawa, Ottawa, Canada. His academic background includes a PhD. in molecular biology, a MPA in Public Administration and post-doctoral training in both Policy Studies and Risk Communication. He focuses on emerging issues including: genomics, bioinformatics, zoonotic dis-

eases, medical nanotechnology and infectious disease communication. He has published over 70 peer reviewed papers and is author of "SARS Unmasked" (2010, McGill Queens University Press), a comprehensive book on infectious disease risk management in Canada. He acts as a reviewer for several health and public policy journals and works extensively with the Canadian government on infectious disease risk assessments.

Contents

**Preface IX** 

Chapter 1 **The Risk of Blood-Borne** 

**Part 1 Typical Health Risk Assessment** 

Chapter 2 **Professional Drivers and Psychoactive** 

**Part 2 Health Risk Assessment Case** 

Chapter 3 **Xenotropic Murine Leukemia** 

Chapter 5 **Safety, Security and Quality:** 

Nicola Petti and Lorenzo Rubinetto

**Studies for Emerging Risks 29** 

**Virus-Related Virus as a Case Study:** 

Marian Laderoute, Jun Wu, Willy Aspinall,

Chapter 4 **Ultrafine and Fine Aerosol Deposition in the Nasal** 

Jinxiang Xi, JongWon Kim and Xiuhua A. Si

**Lessons from GMO Risk Assessments 73** 

Alice Benessia and Giuseppe Barbiero

Daniel Krewski and Peter R. Ganz

**and a 53-Year-Old Male 47** 

**Using a Precautionary Risk Management Approach for Emerging Blood-Borne Pathogens in Canada 31**  Michael G. Tyshenko, Susie ElSaadany, Tamer Oraby,

**Airways of a 9-Month-Old Girl, a 5-Year-Old Boy** 

**Case Studies for Novel Risks 1** 

**Viral Infection due to Syringe Re-Use 3**  Tamer Oraby, Susie Elsaadany, Robert Gervais,

**Substances Consumption: First Results from Medical Surveillance at the Workplace in Italy 21**  Gian Luca Rosso, Mauro Feola, Maria Paola Rubinetto,

Mustafa Al-Zoughool, Michael G. Tyshenko, Lynn Johnston, Mel Krajden, Dick Zoutman, Jun Wu and Daniel Krewski

## Contents

#### **Preface XI**

#### **Part 1 Typical Health Risk Assessment Case Studies for Novel Risks 1**


#### **Part 2 Health Risk Assessment Case Studies for Emerging Risks 29**


X Contents

#### **Part 3 Improving Future Risk Assessment Analyses 109**

Chapter 6 **Breast Cancer Prognostication and Risk Prediction in the Post-Genomic Era 111**  Xi Zhao, Ole Christian Lingjærde and Anne-Lise Børresen-Dale

#### Chapter 7 **Physics of Open Systems: A New Approach to Use Genomics Data in Risk Assessment 135**  Viacheslav Ageev, Boric Fomin, Oleg Fomin, Tamara Kachanova, Chao Chen, Maria Spassova and Leonid Kopylev

Chapter 8 **New Models for the** *In Vitro* **Study of Liver Toxicity: 3D Culture Systems and the Role of Bioreactors 161**  Giovanna Mazzoleni and Nathalie Steimberg

## Preface

There are a myriad number of different types of risks that, as individuals, we face every day that impact human health. Exposure to hazards can result from the natural and build environments with modulation of this exposure due to other factors such as our biology (eg. genetics, age, gender and comorbid conditions) and social interactions (eg. lifestyle choices and our level of risk acceptance). A broad population health approach includes determinants of health, this is the collective label given to factors and conditions that are thought to have an influence on health. Using such an extended understanding of the risk issue and its determinants of health context are very important to the scope of risk assessment efforts.

Many risks that we face on a daily basis may be unavoidable, so there is an expectation by individuals that the level of risk is being managed and reduced to safe levels through evidence-based risk assessments and public health interventions. There has been a growing recognition that risks need to be viewed in their public health context to ensure that the most important risks are prioritized and addressed. Under a broader public health imperative, risk assessments are used as an important process to quantify the probability of harmful effects to individuals, sub-populations (eg. vulnerable patient groups) or entire populations. Thus, both quantitative and qualitative risk assessments help to evaluate the risks associated with hazards, help to prioritize the risks, and allow for cost-effective option generation to eliminate or control the hazards.

The completion of risk assessments, appropriate in scope, can help decision-makers to select the most efficient and effective evidence based strategies. With limited government health budgets challenged by an aging population demographic such an understanding can improve resource allocation. Risk assessment must be sufficiently broad to ensure adequate understanding of the risk and to identify effective risk management options.

This book presents an interesting and diverse collection of health risk assessments and health risk management research for known, and emerging risks that span a continuum towards future developments that aim to improve risk assessment analyses. Two case studies for existing health risks are presented in the first section and utilize surveys and look-back modeling methods. The second section deals with

#### X Preface

emerging health risk and provides three case studies and demonstrates the difficulties of assessing new risks when the scientific evidence base is limited. The third section provides case studies that challenge traditional assessments to improve future risk assessment methods.

Preface XI

infant, child, and an adult to characterize breathing resistance, airflow dynamics, and particle transport/deposition during inhalation. Such a comprehensive model allows for the modeled deposition of submicrometer aerosols (nanosized particles and particulate matter sizes larger that nano to determine the total deposition as well as localized deposition of particles). The results are important, prospectively, since they may lead to a better understanding of the developmental respiratory physiology and the associated effects on children's health response to environmental pollutants, or the medical outcome from inhalation therapy for infants and children from nanoparticlecontaining medicines. The model also has applications for adults who may experience high nanoparticle exposure through the workplace as an occupational hazard and may

The fifth chapter by **Benessia and Barbiero** discusses the epistemic and normative issues surrounding the uncertainty, risks and knowledge gaps of genetically modified organisms (GMOs). Genetically modified salmon is the first animal seeking regulatory approval but it is still unapproved after more than a decade of risk assessments. The authors use this as a case study to explore the context and "ways of knowing" surrounding risk assessments to show how regulatory oversight and policy that are framed for GMOs may be inadequate for providing assurances of long term environmental and health safety. The interplay between science, society and governance is important in the area of GMOs, which once approved and released into the environment, may have unexpected and uncontrollable impacts. The salmon contains genetic modifications for fast growth which could have unknown effects on wild populations should they be released into the wild. The issue focuses the concerns over global environmental safety and security stemming from the risk assessments of not only GM salmon but all follow-on genetic modifications to animals. The authors conclude that the way in which risk assessments are completed for GMOs presents a paradox to environmental and public safety. The solution to this problem suggested by the authors is to invoke a more transparent, wider public democratization of the issues surrounding GMOs to incorporate local, social, cultural and ecological public values. The chapter reinforces the theme of incorporating broader determinants of

health similar to the other case studies dealing with emerging health risks.

breast cancer therapy and gene expression profiling.

Looking towards the future of risk assessments, the final section deals with improving health risk assessments through the use of personalized genomics, new approaches using genomics data in risk assessments, and new *in silico* modeling for toxicogenomics analyses. The sixth chapter by **Zhao et al.** presents microarray expression profiling in breast cancer risk assessment. The chapter reviews and describes breast cancer microarrays, the algorithms used, the established gene signature, and the limitations with combining gene signatures for improved prediction of cancer therapy. The authors provide a potential improvement for breast cancer gene-expression signature analyses that will be of great interest to those involved in

be exposed to synthetic nanoparticles of this concentration.

Case studies for existing risks in the first section include drug use in Italian professional delivery truck drivers and using look-back risk assessment for syringe reuse in Canada. The first chapter by **Oraby et al.** describes the occurrence of syringe reuse reported in a Canadian health care setting on approximately 1,400 patients in the province of Alberta. Multiple syringe re-use events may act as a vector to transmit both RNA and DNA viruses. This look-back study analyzed the risks for Hepatitis B (HBV), Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV) using a probabilistic model with sensitivity analyses.

The second chapter case study by **Rosso et al.** presents a medical survey that tests professional drivers for the presence of various psychoactive substances. Positives were identified by using a commercially available immunoassay rapid kit test which indicates consumption of psychoactive drugs. This is of interest and important since the dependence on drugs may pose a risk to drivers in their profession affecting their reaction time and driving judgment. This is one of the first and important contributions to the literature in this area. The study is of high importance as drivers under the influence of psychoactive drugs may endanger themselves or others if impaired at the jobsite.

Case studies for emerging risks in the second section include evidence-based precautionary interventions to safeguard blood supplies, the evaluation of nanoparticle deposition in the lung and nasal airways and the discourse surrounding emerging potential health risks of genetically modified animals consumed as food. The third chapter by **Tyshenko et al.** reviews a case study concerning xenotropic murine leukemia virus-related virus (XMRV) and its emergence as a potential new blood pathogen that occurred in 2009; a lack of information for decision-making confounded risk assessment and early management decision-making. The chapter provides insight into the early assessment process and the application of precaution, an often poorly described management action rarely captured in peer review literature. The situation surrounding this potential new threat to blood safety was largely resolved in mid-2011 when it was determined that the virus was an artifact from contaminated patient samples and from contamination stemming from a diagnostic test kit widely used by researchers. The case study provides good assessment and management insight into the application of early precautionary action and the use of expert opinion for proactive risk management of emerging blood-borne pathogens.

The fourth chapter by **Jinxiang et al.** assesses the airflow and aerosol dynamic characteristics within the nasal cavity for three different individuals. The study assesses and models the physical dimensions of the nasal airway and lungs for an infant, child, and an adult to characterize breathing resistance, airflow dynamics, and particle transport/deposition during inhalation. Such a comprehensive model allows for the modeled deposition of submicrometer aerosols (nanosized particles and particulate matter sizes larger that nano to determine the total deposition as well as localized deposition of particles). The results are important, prospectively, since they may lead to a better understanding of the developmental respiratory physiology and the associated effects on children's health response to environmental pollutants, or the medical outcome from inhalation therapy for infants and children from nanoparticlecontaining medicines. The model also has applications for adults who may experience high nanoparticle exposure through the workplace as an occupational hazard and may be exposed to synthetic nanoparticles of this concentration.

X Preface

assessment methods.

impaired at the jobsite.

pathogens.

probabilistic model with sensitivity analyses.

emerging health risk and provides three case studies and demonstrates the difficulties of assessing new risks when the scientific evidence base is limited. The third section provides case studies that challenge traditional assessments to improve future risk

Case studies for existing risks in the first section include drug use in Italian professional delivery truck drivers and using look-back risk assessment for syringe reuse in Canada. The first chapter by **Oraby et al.** describes the occurrence of syringe reuse reported in a Canadian health care setting on approximately 1,400 patients in the province of Alberta. Multiple syringe re-use events may act as a vector to transmit both RNA and DNA viruses. This look-back study analyzed the risks for Hepatitis B (HBV), Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV) using a

The second chapter case study by **Rosso et al.** presents a medical survey that tests professional drivers for the presence of various psychoactive substances. Positives were identified by using a commercially available immunoassay rapid kit test which indicates consumption of psychoactive drugs. This is of interest and important since the dependence on drugs may pose a risk to drivers in their profession affecting their reaction time and driving judgment. This is one of the first and important contributions to the literature in this area. The study is of high importance as drivers under the influence of psychoactive drugs may endanger themselves or others if

Case studies for emerging risks in the second section include evidence-based precautionary interventions to safeguard blood supplies, the evaluation of nanoparticle deposition in the lung and nasal airways and the discourse surrounding emerging potential health risks of genetically modified animals consumed as food. The third chapter by **Tyshenko et al.** reviews a case study concerning xenotropic murine leukemia virus-related virus (XMRV) and its emergence as a potential new blood pathogen that occurred in 2009; a lack of information for decision-making confounded risk assessment and early management decision-making. The chapter provides insight into the early assessment process and the application of precaution, an often poorly described management action rarely captured in peer review literature. The situation surrounding this potential new threat to blood safety was largely resolved in mid-2011 when it was determined that the virus was an artifact from contaminated patient samples and from contamination stemming from a diagnostic test kit widely used by researchers. The case study provides good assessment and management insight into the application of early precautionary action and the use of expert opinion for proactive risk management of emerging blood-borne

The fourth chapter by **Jinxiang et al.** assesses the airflow and aerosol dynamic characteristics within the nasal cavity for three different individuals. The study assesses and models the physical dimensions of the nasal airway and lungs for an The fifth chapter by **Benessia and Barbiero** discusses the epistemic and normative issues surrounding the uncertainty, risks and knowledge gaps of genetically modified organisms (GMOs). Genetically modified salmon is the first animal seeking regulatory approval but it is still unapproved after more than a decade of risk assessments. The authors use this as a case study to explore the context and "ways of knowing" surrounding risk assessments to show how regulatory oversight and policy that are framed for GMOs may be inadequate for providing assurances of long term environmental and health safety. The interplay between science, society and governance is important in the area of GMOs, which once approved and released into the environment, may have unexpected and uncontrollable impacts. The salmon contains genetic modifications for fast growth which could have unknown effects on wild populations should they be released into the wild. The issue focuses the concerns over global environmental safety and security stemming from the risk assessments of not only GM salmon but all follow-on genetic modifications to animals. The authors conclude that the way in which risk assessments are completed for GMOs presents a paradox to environmental and public safety. The solution to this problem suggested by the authors is to invoke a more transparent, wider public democratization of the issues surrounding GMOs to incorporate local, social, cultural and ecological public values. The chapter reinforces the theme of incorporating broader determinants of health similar to the other case studies dealing with emerging health risks.

Looking towards the future of risk assessments, the final section deals with improving health risk assessments through the use of personalized genomics, new approaches using genomics data in risk assessments, and new *in silico* modeling for toxicogenomics analyses. The sixth chapter by **Zhao et al.** presents microarray expression profiling in breast cancer risk assessment. The chapter reviews and describes breast cancer microarrays, the algorithms used, the established gene signature, and the limitations with combining gene signatures for improved prediction of cancer therapy. The authors provide a potential improvement for breast cancer gene-expression signature analyses that will be of great interest to those involved in breast cancer therapy and gene expression profiling.

#### XII Preface

The seventh chapter by **Ageev et al.** uses formaldehyde exposure as a case study. The formaldehyde exposure data is re-analyzed to reveal exposure effects on gene expression levels not previously observed with the datasets. This type of analysis can provide better estimates of gene expression activity at low doses for well characterized chemical hazards.

The final chapter by **Mazzoleni and Steimberg** provides an excellent overview of current and new models for the study of liver toxicity with a focus on cultured cells and culture methods. The use of new 3D culture and emerging bioreactor models for toxicity testing fits well with the future paradigm of toxicity risk assessments that seek to move towards *in vitro* and *in silico* methods.

Overall, the book is a collection of interesting case studies that provides a continuum of risk assessment methods and epistemology for known, emerging and future risks. The book will be of interest to risk assessors, epidemiologists, toxicologists, and anyone involved in health policy or health studies.

> **Michael G. Tyshenko PhD, MPA**  McLaughlin Chair in Biological Risk Assessment Institute of Population Health, University of Ottawa, Ottawa, Ontario Canada

XII Preface

chemical hazards.

to move towards *in vitro* and *in silico* methods.

anyone involved in health policy or health studies.

The seventh chapter by **Ageev et al.** uses formaldehyde exposure as a case study. The formaldehyde exposure data is re-analyzed to reveal exposure effects on gene expression levels not previously observed with the datasets. This type of analysis can provide better estimates of gene expression activity at low doses for well characterized

The final chapter by **Mazzoleni and Steimberg** provides an excellent overview of current and new models for the study of liver toxicity with a focus on cultured cells and culture methods. The use of new 3D culture and emerging bioreactor models for toxicity testing fits well with the future paradigm of toxicity risk assessments that seek

Overall, the book is a collection of interesting case studies that provides a continuum of risk assessment methods and epistemology for known, emerging and future risks. The book will be of interest to risk assessors, epidemiologists, toxicologists, and

**Michael G. Tyshenko PhD, MPA** 

Ottawa, Ontario

Canada

McLaughlin Chair in Biological Risk Assessment Institute of Population Health, University of Ottawa,

**Part 1** 

**Typical Health Risk Assessment** 

**Case Studies for Novel Risks** 

## **Part 1**

**Typical Health Risk Assessment Case Studies for Novel Risks** 

**1** 

*Canada* 

**The Risk of Blood-Borne Viral Infection** 

*McLaughlin Centre for Population Health Risk Assessment, University of Ottawa,* 

Transmission of viral and bacterial infections through the practice of syringe re-use has been repeatedly documented (American Society of Anesthesiologists, 1999) and controlled experiments have demonstrated that a syringe barrel becomes contaminated with microbes

In the fall of 2008, light was shed on the practice of syringe re-use occurring in western Canada (Government of Alberta, 2009). In this situation, syringes had been re-used between patients to administer sedating medication through patient intravenous (IV) lines (Government of Alberta, 2009). Later it was reported that other incidents of syringe re-use had occurred in Canada (CBC News-Edmonton, 2008a;CBC News-Edmonton, 2008b). The question arose of whether this practice may have resulted in the transmission of bloodborne pathogens to patients and, if so, how many and with what level of risk. To answer this question, a retrospective study involving approximately 1,400 patients was undertaken (Government of Alberta, 2009). However, questions were also raised as to whether estimates based on modeling scenarios could provide information to guide decisions on the need for

Risk assessments have been carried out almost concurrently with the underlying study; they gave various and different conclusions (Population Health Branch-Saskatchewan Health, 2009; Sikora et al., 2010). Contrary to our study where we considered the Canadian nation as a whole, the Population Health Branch-Saskatchewan study looked at only a province-wide risk assessment for Saskatchewan based on the same methods in Sikora et al. (2010); they concluded that the blood-borne viral infection was negligible (Population Health Branch-

\* Susie Elsaadany2,\*\*, Robert Gervais2, Mustafa Al-Zoughool1, Michael G. Tyshenko1, Lynn Johnston3,

*3Queen Elizabeth II Health Sciences Centre, Nova Scotia, Canada, 4BC Centre for Disease Control, University of British Columbia, Vancouver, Canada, 5Medical Microbiology and Infection Control, Queen's University, Ontario, Canada, 6Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa,* 

*1McLaughlin Center for Population Health Risk Assessment, University of Ottawa, Ottawa, Canada, 2Public Health Agency of Canada, Ottawa, Canada,* 

after multiple re-uses (Lessard et al., 1988; Perceval, 1980).

Mel Krajden4, Dick Zoutman5, Jun Wu2 and Daniel Krewski1,6

**1. Introduction** 

look-backs.

*Canada* 

\*\* Corresponding Author

**due to Syringe Re-Use** 

\*\* Tamer Oraby et al.\*

## **The Risk of Blood-Borne Viral Infection due to Syringe Re-Use**

\*\* Tamer Oraby et al.\*

*McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Canada* 

#### **1. Introduction**

Transmission of viral and bacterial infections through the practice of syringe re-use has been repeatedly documented (American Society of Anesthesiologists, 1999) and controlled experiments have demonstrated that a syringe barrel becomes contaminated with microbes after multiple re-uses (Lessard et al., 1988; Perceval, 1980).

In the fall of 2008, light was shed on the practice of syringe re-use occurring in western Canada (Government of Alberta, 2009). In this situation, syringes had been re-used between patients to administer sedating medication through patient intravenous (IV) lines (Government of Alberta, 2009). Later it was reported that other incidents of syringe re-use had occurred in Canada (CBC News-Edmonton, 2008a;CBC News-Edmonton, 2008b). The question arose of whether this practice may have resulted in the transmission of bloodborne pathogens to patients and, if so, how many and with what level of risk. To answer this question, a retrospective study involving approximately 1,400 patients was undertaken (Government of Alberta, 2009). However, questions were also raised as to whether estimates based on modeling scenarios could provide information to guide decisions on the need for look-backs.

Risk assessments have been carried out almost concurrently with the underlying study; they gave various and different conclusions (Population Health Branch-Saskatchewan Health, 2009; Sikora et al., 2010). Contrary to our study where we considered the Canadian nation as a whole, the Population Health Branch-Saskatchewan study looked at only a province-wide risk assessment for Saskatchewan based on the same methods in Sikora et al. (2010); they concluded that the blood-borne viral infection was negligible (Population Health Branch-

<sup>\*</sup> Susie Elsaadany2,\*\*, Robert Gervais2, Mustafa Al-Zoughool1, Michael G. Tyshenko1, Lynn Johnston3, Mel Krajden4, Dick Zoutman5, Jun Wu2 and Daniel Krewski1,6

*<sup>1</sup>McLaughlin Center for Population Health Risk Assessment, University of Ottawa, Ottawa, Canada, 2Public Health Agency of Canada, Ottawa, Canada,* 

*<sup>3</sup>Queen Elizabeth II Health Sciences Centre, Nova Scotia, Canada, 4BC Centre for Disease Control, University of British Columbia, Vancouver, Canada, 5Medical Microbiology and Infection Control, Queen's University, Ontario, Canada, 6Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada* 

<sup>\*\*</sup> Corresponding Author

Risk of Syringe Re-Use in Canada 5

valves were taken into account.

patients are independent.

**2.3 Hazard and risk characterization** 

"wash-out").

syringe, �������

c. Assumptions on patient characteristics and needs

d. Assumptions on the nature of the viruses targeted

was used, which consisted of an infusion bag, and a length of tubing long enough to have a significant fluid flow/possibility of wash-out between two sites of injection; one proximal injection site at the bag, one distal at the catheter. No filters, locks or check

Patients treated are randomly selected from a high risk population on which the syringe could have been re-used; virus carriers can potentially infect any of the subsequent patients in a group before a syringe is disposed; and the events of source patient infection, virus contamination of the syringe and transmitting virus to subsequent

In accordance with worst case scenario, the presence of virus in the blood of a model

This assessment addresses only potential infection with re-used syringes. Other potential sources of contamination, in particular the contamination of multi-dose medicine vials, are

The model used probabilistic designed to assess the risk of HIV, HCV and HBV infection attributed to syringe re-use on multiple patients. The risk of viral contamination and subsequent patient infection only arises if the syringe is re-used. It is also changing with the number of syringe re-uses (�), or equivalently with the number of previous infectious patients on whom the syringe was re-used ���� ��� �����. The risk is lowered, but not completely eliminated, by a log reduction factor, if the syringe is flushed (this is known as

If � patients were known to have been exposed to a re-used syringe, the risk of viral infection for the �th patient in the sequence of � patients could be determined. The risk that the patient number � will contract the viral infection from one of the previous ��1 patients is given by:

transmitting the disease after ����1 usages. The individual risk (����), or the risk

�

���

Here, � can be denoted as the number of injections until syringe replacement. The random variable � follows a geometric distribution with mean number of re-uses � given that � �

� � �� �

���

������� �

��� � � ��� � � 2� � � � (1)

� ������

is the probability of contaminating the

is the probability of

(2)

�������

patient is binary (either yes or no); the infectivity of the virus is 100%.

not considered due to the lack of sufficient information in the literature.

�� � ������ � �1 �� �1 � ���� � ������� � ����

imposed on a patient that underwent syringe re-use practice, is given by:

���� � ����������� � �<sup>1</sup>

is the probability of being susceptible and ����

���

with �� � �, where ���� is the prevalence, �������

 2. Thus, the individual risk is given by:

Saskatchewan Health, 2009). The model in Sikora et al., (2010) is a multiplicative model of four probabilities. It also considers only the risk that one patient is imposing on one other patient without taking into account the number of times the syringe may have been re-used in between them.

A novel but simple probabilistic model is established in the underlying study to reflect more accurately the practical situation that is occurring. The risk of viral infection at any time of re-use depends not only on the prevalence and susceptibility but also the number of times the syringe barrel was re-used before that time. Uncertainty and sensitivity analyses were carried out here to incorporate the lack of knowledge about different parameters, e.g. probability of contaminating a syringe, and assess their influence on the risk.

### **2. Methods**

Blood-borne diseases can be transmitted through contact with bodily fluids, most often blood; they include Hepatitis B (HBV), Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV). A probabilistic model was designed for the purpose of assessing the risk of these three viral infections due to re-use of syringes on multiple patients. The values for multiple risk factor variables used in this quantitative risk assessment were obtained from the literature (where data existed), consensus of opinions from a nationally commissioned expert working group, (Public Health Agency of Canada, 2008; Public Health Agency of Canada, 2009) and from information extracted from recently documented cases of syringe re-use in Canada and other countries.

The risk assessment consisted of three main areas: 1) Issue identification, 2) Exposure and hazard assessment, and 3) Hazard and risk characterization.

#### **2.1 Issue identification**

There are many different types of IV apparatus systems, with possibly thousands of combinations of add-on auxiliary components. This assessment investigated the constituents of a basic IV administration apparatus, and the components of a generic disposable plastic syringe to choose a "most common method" used by health care workers to deliver medications to patients via the intravenous route. The apparatus chosen is described in the exposure and hazard assessment section below.

#### **2.2 Exposure and hazard assessment**

To provide preliminary estimates of the level of exposure to viral pathogens via plastic syringe re-use, assumptions in the following categories were defined:

a. Assumptions of health care worker (HCW) practices

The precise number of times an HCW will re-use a syringe is unknown, and independent of the number of times the syringe was re-used previously.

b. Assumptions about medical device/instrument properties

Contamination of the syringe/tubing via fluid backflow was estimated based on the proximity of the medication injection site to the patient. A generic instrument set up

Saskatchewan Health, 2009). The model in Sikora et al., (2010) is a multiplicative model of four probabilities. It also considers only the risk that one patient is imposing on one other patient without taking into account the number of times the syringe may have been re-used

A novel but simple probabilistic model is established in the underlying study to reflect more accurately the practical situation that is occurring. The risk of viral infection at any time of re-use depends not only on the prevalence and susceptibility but also the number of times the syringe barrel was re-used before that time. Uncertainty and sensitivity analyses were carried out here to incorporate the lack of knowledge about different parameters, e.g.

Blood-borne diseases can be transmitted through contact with bodily fluids, most often blood; they include Hepatitis B (HBV), Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV). A probabilistic model was designed for the purpose of assessing the risk of these three viral infections due to re-use of syringes on multiple patients. The values for multiple risk factor variables used in this quantitative risk assessment were obtained from the literature (where data existed), consensus of opinions from a nationally commissioned expert working group, (Public Health Agency of Canada, 2008; Public Health Agency of Canada, 2009) and from information extracted from recently documented cases of syringe

The risk assessment consisted of three main areas: 1) Issue identification, 2) Exposure and

There are many different types of IV apparatus systems, with possibly thousands of combinations of add-on auxiliary components. This assessment investigated the constituents of a basic IV administration apparatus, and the components of a generic disposable plastic syringe to choose a "most common method" used by health care workers to deliver medications to patients via the intravenous route. The apparatus chosen is described in the

To provide preliminary estimates of the level of exposure to viral pathogens via plastic

The precise number of times an HCW will re-use a syringe is unknown, and

Contamination of the syringe/tubing via fluid backflow was estimated based on the proximity of the medication injection site to the patient. A generic instrument set up

syringe re-use, assumptions in the following categories were defined:

independent of the number of times the syringe was re-used previously.

a. Assumptions of health care worker (HCW) practices

b. Assumptions about medical device/instrument properties

probability of contaminating a syringe, and assess their influence on the risk.

in between them.

**2. Methods** 

re-use in Canada and other countries.

**2.1 Issue identification** 

hazard assessment, and 3) Hazard and risk characterization.

exposure and hazard assessment section below.

**2.2 Exposure and hazard assessment** 

was used, which consisted of an infusion bag, and a length of tubing long enough to have a significant fluid flow/possibility of wash-out between two sites of injection; one proximal injection site at the bag, one distal at the catheter. No filters, locks or check valves were taken into account.

c. Assumptions on patient characteristics and needs

Patients treated are randomly selected from a high risk population on which the syringe could have been re-used; virus carriers can potentially infect any of the subsequent patients in a group before a syringe is disposed; and the events of source patient infection, virus contamination of the syringe and transmitting virus to subsequent patients are independent.

d. Assumptions on the nature of the viruses targeted

In accordance with worst case scenario, the presence of virus in the blood of a model patient is binary (either yes or no); the infectivity of the virus is 100%.

This assessment addresses only potential infection with re-used syringes. Other potential sources of contamination, in particular the contamination of multi-dose medicine vials, are not considered due to the lack of sufficient information in the literature.

#### **2.3 Hazard and risk characterization**

The model used probabilistic designed to assess the risk of HIV, HCV and HBV infection attributed to syringe re-use on multiple patients. The risk of viral contamination and subsequent patient infection only arises if the syringe is re-used. It is also changing with the number of syringe re-uses (�), or equivalently with the number of previous infectious patients on whom the syringe was re-used ���� ��� �����. The risk is lowered, but not completely eliminated, by a log reduction factor, if the syringe is flushed (this is known as "wash-out").

If � patients were known to have been exposed to a re-used syringe, the risk of viral infection for the �th patient in the sequence of � patients could be determined. The risk that the patient number � will contract the viral infection from one of the previous ��1 patients is given by:

$$R\_k = P^{\{\text{sus}\}} \times \left[ 1 - \prod\_{f=1}^{k-1} \left( 1 - Precv \times P^{\{\text{cont}\}} \times P\_{k-f}^{\{\text{trans}\}} \right) \right], \text{for } k = 2, \ldots, \mathfrak{s} \tag{1}$$

with �� � �, where ���� is the prevalence, ������� is the probability of contaminating the syringe, ������� is the probability of being susceptible and ���� ������� is the probability of transmitting the disease after ����1 usages. The individual risk (����), or the risk imposed on a patient that underwent syringe re-use practice, is given by:

$$Risk = P(prectice) \times \sum\_{s=2}^{\infty} \frac{1}{s} \sum\_{k=1}^{s} R\_k \times P\{\mathcal{S} = s\} \tag{2}$$

Here, � can be denoted as the number of injections until syringe replacement. The random variable � follows a geometric distribution with mean number of re-uses � given that � � 2. Thus, the individual risk is given by:

Risk of Syringe Re-Use in Canada 7

The parameter "ܲݎimmu" represents the percentage of individuals who display HBV immunity after having received HBV vaccination. The immunogenicity of the HBV vaccine is not 100%, and requires multiple dosing to achieve protective antibody levels (≥ 10 IU/L) (Mackie et al., 2009). The primary determinant of seroprotection is the age at which an individual is vaccinated. The average HBV seroprotection rates as described by the Canadian Immunization

**Age Range (years) Seroprotection Rates**  >2 95% 5-15 99% 20-29 95% 30-39 90% 40-49 86% 50-59 71% ≥ 60 50% to 70% Table 2. Seroprotection rates based on age groups following HBV vaccination, data from The

Recipient factors other than age also affect the rate of seroprotection in vaccinated individuals. For example, the antibody response is lower in patients with diabetes mellitus (range: 70% to 80%), renal failure (range: 60% to 70%) and chronic liver disease (range: 60% to 70%). Based on these factors, as well as vaccination uptake in the population, the expert group working on this assessment concluded that approximately 47% (range: 46% to 48%) of the general population is susceptible to HBV infection due to the absence of protective levels of antibodies to HBV in

The parameter "ܲݎimmu and infected" represents the percentage of individuals who are HBV infected, and who have also been vaccinated against HBV, as of the year 2008. The value was determined through expert consensus of a nationally organized working group (Public

Finally, a set of input distributions needed to be created for each variable, in order to run the MCS analysis. Using information provided by health care experts (Public Health Agency of Canada, 2009), we arrived at a set of distributions to address the uncertainty involved in

Scenario analysis was conducted for each blood-borne viral infection using different input values and distributions (Table 1). For the three blood-borne viral infections, the model was most sensitive to changes in disease prevalence. For example, changing the prevalence of HIV from 0.004 to 0.015 increased the individual risk by about 4 times (0.161 and 0.596, respectively) for a value of average syringe re-use of 4 and a wash-out factor of 100. Similarly for HBV, increasing the prevalence from 0.005 to 0.030 increased the individual risk from 6.911 to 43.60, when using an average value of syringe re-use of 4 and a wash-out factor of 100. The increase in risk is almost linear in the disease prevalence, which is

Guide (Public Health Agency of Canada, 2006) are outlined in Table 2.

Canadian Immunization Guide (Public Health Agency of Canada, 2006)

the year 2008 (Mackie et al., 2009; Public Health Agency of Canada, 2006).

Health Agency of Canada, 2008).

supported by the sensitivity analysis (Appendix 2).

syringe re-use (Table 1).

**3. Results** 

$$Risk = P\{priceice\} \times \frac{1}{M-1} \times \sum\_{s=2}^{\infty} \frac{1}{s} \sum\_{k=1}^{S} R\_k \times \left(1 - \frac{1}{M-1}\right)^{s-2} \tag{3}$$

where ����������� is the probability of syringe re-use practice. While the derivation of the three equations is straightforward, proofs are given in Appendix 1 for completion. Table 1 describes the model components and the values used to run the analysis.


\* Pert (min, most likely, max), Triangular (min, most likely, max) and Uniform (min, max)

Table 1. Model components with the values and distributions used for the MCS analysis

Monte Carlo Simulations (MCS) were necessary to incorporate uncertainties surrounding syringe re-use practice. MCS sometimes requires specific computational software and platforms. In this study, we have used Monte Carlo Simulations implemented on the R statistical software (R Development Core Team, 2010).

<sup>1</sup> Refer to Table 2.

<sup>2</sup> The efficiency of transmission is calculated by multiplying transmission percentage by log reduction (wash-out) factors.

���

where ����������� is the probability of syringe re-use practice. While the derivation of the three equations is straightforward, proofs are given in Appendix 1 for completion. Table 1

**Component Variable Range or Description Probability** 

Syringe re-use practice ����������� 2.2% - 60% Pert (2.2%, 20%, 60%) Wash-out factor � � 1�� Log-reduction Uniform (1,2)

HBV immunity ���immu 47%1 Triangular (46%, 47%,
